Compounds and compositions as protein kinase inhibitors

ABSTRACT

The invention relates to compounds of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein the substituents X 1 , R 1 , R 2 , R 3  and R 4  have the meaning as set forth and explained in the description of the invention, to processes for the preparation of these compounds, pharmaceutical compositions containing same, the use thereof optionally in combination with one or more other pharmaceutically active compounds for the therapy of a disease which responds to an inhibition of protein kinase activity, and a method for the treatment of such a disease.

The invention relates to novel compounds, formulations, methods anduses. More particularly it relates to compounds, which may be describedas heteroaryl aryl ureas, useful for the treatment of protein kinasedependent diseases, or for the manufacture of pharmaceuticalcompositions for use in the treatment of said diseases. The inventionfurther relates to methods of use of such compounds in the treatment ofsaid diseases, pharmaceutical preparations comprising heteroaryl arylureas, and processes for the manufacture of heteroaryl aryl ureas. Theinvention relates to other subject matter as disclosed below.

BACKGROUND

Protein kinases (PKs) are enzymes which catalyze the phosphorylation ofspecific serine, threonine or tyrosine residues in cellular proteins.These post-translational modifications of substrate proteins act asmolecular switch regulating cell proliferation, activation and/ordifferentiation. Aberrant or excessive PK activity has been observed inmany disease states including benign and malignant proliferativedisorders. In many cases, it has been possible to treat diseases invitro and in many cases in vivo, such as proliferative disorders, bymaking use of PK inhibitors.

The kinases fall largely into two groups, those specific forphosphorylating serine and threonine, and those specific forphosphorylating tyrosine. Some kinases, referred to as “dualspecificity” kinases, are able to phosphorylate tyrosine as well asserine/threonine residues.

Protein kinases can also be characterized by their location within thecell. Some kinases are transmembrane receptor proteins capable ofbinding ligands external to the cell membrane. Binding the ligandsalters the receptor protein kinase's catalytic activity. Others arenon-receptor proteins lacking a transmembrane domain and yet others areecto-kinases that have a catalytic domain on the extracellular (ecto)portion of a transmembrane protein or which are secreted as solubleextracellular proteins.

Many kinases are involved in regulatory cascades where their substratesmay include other kinases whose activities are regulated by theirphosphorylation state. Thus, activity of a downstream effector ismodulated by phosphorylation resulting from activation of the pathway.

Receptor protein tyrosine kinases (RPTKs) are a sub-class oftransmembrane-spanning receptors endowed with intrinsic,ligand-stimulatable tyrosine kinase activity. RPTK activity is tightlycontrolled. When mutated or altered structurally, RPTKs can becomepotent oncoproteins, causing cellular transformation. In principle, forall RPTKs involved in cancer, oncogenic deregulation results from reliefor perturbation of one or several of the autocontrol mechanisms thatensure the normal repression of catalytic domains. More than half of theknown RPTKs have been repeatedly found in either mutated oroverexpressed forms associated with human malignancies (includingsporadic cases; Blume-Jensen et al., Nature 411: 355-365 (2001)).

RPTK over expression leads to constitutive kinase activation byincreasing the concentration of dimers. Examples are Neu/ErbB2 andepidermal growth factor receptor (EGFR), which are often amplified inbreast and lung carcinomas and the fibroblast growth factors (FGFR)associated with skeletal and proliferative disorders (Blume-Jensen etal., 2001).

Angiogenesis is the mechanism by which new capillaries are formed fromexisting vessels. When required, the vascular system has the potentialto generate new capillary networks in order to maintain the properfunctioning of tissues and organs. In the adult, however, angiogenesisis fairly limited, occurring only in the process of wound healing andneovascularization of the endometrium during menstruation. See Merenmieset al., Cell Growth & Differentiation, 8, 3-10 (1997). On the otherhand, unwanted angiogenesis is a hallmark of several diseases, such asretinopathies, psoriasis, rheumatoid arthritis, age-related maculardegeneration (AMD), and cancer (solid tumors). Folkman, Nature Med., 1,27-31 (1995). Protein kinases which have been shown to be involved inthe angiogenic process include three members of the growth factorreceptor tyrosine kinase family: VEGF-R2 (vascular endothelial growthfactor receptor 2, also known as KDR (kinase insert domain receptor) andas FLK-1); FGF-R (fibroblast growth factor receptor); and TEK (alsoknown as Tie-2).

TEK (also known as Tie-2) is a receptor tyrosine kinase expressed onlyon endothelial cells which has been shown to play a role inangiogenesis. The binding of the factor angiopoietin-1 results inautophosphorylation of the kinase domain of TEK and results in a signaltransduction process which appears to mediate the interaction ofendothelial cells with peri-endothelial support cells, therebyfacilitating the maturation of newly formed blood vessels. The factorangiopoietin-2, on the other hand, appears to antagonize the action ofangiopoietin-1 on TEK and disrupts angiogenesis. Maisonpierre et al.,Science, 277, 55-60 (1997).

Administration of Ad-ExTek, a soluble adenoviral expressed extracellulardomain of Tie-2, inhibited tumour metastasis when delivered at the timeof surgical excision of primary tumours in a clinically relevant mousemodel of tumor metastasis (Lin et al., Proc Natl Acad Sci USA 95,8829-8834 (1998)). The inhibition of Tie-2 function by ExTek may be aconsequence of sequestration of the angiopoietin ligand and/orheterodimerisation with the native Tie-2 receptor. This studydemonstrates that disruption of Tie-2 signalling pathways, first, may bewell tolerated in healthy organisms and, second, may provide therapeuticbenefit.

The Philadelphia Chromosome is a hallmark for chronic myelogenousleukaemia (CML) and carries a hybrid gene that contains N-terminal exonsof the bcr gene and the major C-terminal part (exons 2-11) of the c-ablgene. The gene product is a 210 kD protein (p210 Bcr-Abl). The Abl-partof the Bcr-Abl protein contains the abl-tyrosine kinase which is tightlyregulated in the wild type c-abl, but constitutively activated in theBcr-Abl fusion protein. This deregulated tyrosine kinase interacts withmultiple cellular signalling pathways leading to transformation andderegulated proliferation of the cells (Lugo et al., Science 247, 1079[1990]).

Mutant forms of the Bcr-Abl protein have also been identified. Adetailed review of Bcr-Abl mutant forms has been published (Cowan-Joneset al, Mini Reviews in Medicinal Chemistry, 2004, 4 285-299).

EphB4 (also named HTK) and its ligand, ephrinB2 (HTKL) have criticalroles in establishing and determining vascular networks. On the venousepithelium, EphB4 is expressed specifically, while, during early stagesof vascular development, ephrinB2 is specifically and reciprocallyexpressed on arterial endothelial cells. Dysfunctional genes lead toembryonic lethality in mice, and the embryos show identical defects informing capillary connections in case of either defect ephrinB2 andEphB4. Both are expressed at the first site of hematopoiesis andvascular development during embryogenesis. An essential role for properhematopoietic, endothelial, hemangioblast and primitive mesodermdevelopment was established. EphB4 deficiency results in an alterationin the mesodermal differentiation outcome of embryonic stem cells.Ectopic expression of EphB4 in mammary tissue results in disorderedarchitecture, abnormal tissue function and a predisposition tomalignancy (see e.g. N. Munarini et al., J. Cell. Sci. 115, 25-37(2002)). From these and other data, it has been concluded thatinadequate EphB4 expression may be involved in the formation ofmalignancies and thus that inhibition of EphB4 can be expected to be atool to combat malignancies, e.g. cancer and the like.

c-Src (also known as p60 c-Src) is cytosolic, non-receptor tyrosinekinase. c-Src is involved in the transduction of mitogenic signals froma number of polypeptide growth factors such as epidermal growth factor(EGF) and platelet-derived growth factor (PDGF). c-Src is over expressedin mammary cancers, pancreatic cancers, neuroblastomas, and others.Mutant c-Src has been identified in human colon cancer. c-Srcphosphorylates a number of proteins that are involved in regulatingcross-talk between the extracellular matrix and the cytoplasmic actincytoskeleton. Modulation cSrc activity could have implications indiseases relating to cell proliferation, differentiation and death. SeeBjorge, J. D., et. al. (2000) Oncogene 19(49):5620-5635; Halpern, M. S.,et. al. (1996) Proc. Natl. Acad. Sci. U.S.A. 93(2), 824-7; Belsches, A.P., et. al. (1997) Frontiers in Bioscience [Electronic Publication]2:D501-D518; Zhan, X., et. al (2001) Chemical Reviews 101: 2477-2496;Haskell, M. D., et. al. (2001) Chemical Reviews 101: 2425-2440.

The fms-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase is nowrecognized to be a critical mediator in the pathogenesis of myeloid andsome lymphoid leukemias. Activation of FLT3 on leukemic cells by FLT3ligand leads to receptor dimerization and signal transduction inpathways that promote cell growth and inhibit apoptosis (Blood, Vol. 98,No. 3, pp. 885-887 (2001)).

Use of tyrosine kinase inhibitors for AML therapy is hindered by theacquisition of mutations in the kinase catalytic domain, and in the caseof BCR-ABL, these mutations confer resistance to imatinib.

FLT3 is widely expressed in AML and some cases of acute lymphocyticleukemia. Activating mutations in FLT3 confer a poor risk in patientswith AML. Thus, FLT3 is a promising target for therapeutic intervention.

Platelet-derived growth factor receptor (PDGFR) tyrosine kinase isexpressed in a numberof tumours such as small-cell lung cancer, prostatecancer, and glioblastoma as well as in the stromal and vascularcompartments of many tumors. Expression of both PDGF and PDGF receptors(PDGFRs) has been observed in pancreatic cancer (Ebert M et al., Int JCancer, 62: 529-535 (1995).

Fibroblast Growth Factors

Normal growth, as well as tissue repair and remodeling, require specificand delicate control of activating growth factors and their receptors.Fibroblast Growth Factors (FGFs) constitute a family of over twentystructurally related polypeptides that are developmentally regulated andexpressed in a wide variety of tissues. FGFs stimulate proliferation,cell migration and differentiation and play a major role in skeletal andlimb development, wound healing, tissue repair, hematopoiesis,angiogenesis, and tumorigenesis (reviewed in Omitz, Novartis Found Symp232: 63-76; discussion 76-80, 272-82 (2001)).

The biological action of FGFs is mediated by specific cell surfacereceptors belonging to the RPTK family of protein kinases. Theseproteins consist of an extracellular ligand binding domain, a singletransmembrane domain and an intracellular tyrosine kinase domain whichundergoes phosphorylation upon binding of FGF. Four FGFRs have beenidentified to date: FGFR1 (also called Flg, fms-like gene, flt-2, bFGFR,N-bFGFR or Cek1), FGFR2 (also called Bek-Bacterial Expressed Kinase-,KGFR, Ksam, Ksaml and Cek3), FGFR3 (also called Cek2) and FGFR4. Allmature FGFRs share a common structure consisting of an amino terminalsignal peptide, three extracellular immunoglobulin-like domains (Igdomain I, Ig domain II, Ig domain III), with an acidic region between Igdomains (the“acidic box” domain), a transmembrane domain, andintracellular kinase domains (Ullrich and Schlessinger, Cell 61: 203,1990; Johnson and Williams (1992) Adv. Cancer Res. 60: 1-41). Thedistinct FGFR isoforms have different binding affinities for thedifferent FGF ligands, thus FGF8 (androgen-induced growth factor) andFGF9 (glial activating factor) appear to have increased selectivity forFGFR3 (Chellaiah et al. J. Biol. Chem. 1994; 269: 11620).

Another major class of cell surface binding sites includes binding sitesfor heparan sulfateproteoglycans (HSPG) that are required for highaffinity interaction and activation of all members of the FGF family.Tissue-specific expression of heparan sulfate structural variants conferligand-receptor specificity and activityof FGFs

FGFR-Related Diseases

Recent discoveries show that a growing number of skeletal abnormalities,including achondroplasia, the most common form of human dwarfism, resultfrom mutations in FGFRs.

Specific point mutations in different domains of FGFR3 are associatedwith autosomal dominant human skeletal disorders includinghypochondroplasia, severe achondroplasia with developmental delay andacanthosis nigricans (SADDAN) and thanatophoric dysplasia (TD)(Cappellen et al., Nature Genetics, 23: 18-20 (1999); Webster et al.,Trends Genetics 13 (5): 178-182 (1997); Tavormina et al., Am. J. Hum.Genet., 64: 722-731 (1999)). FGFR3 mutations have also been described intwo craniosynostosis phenotypes: Muenke coronal craniosynostosis (Belluset al., Nature Genetics, 14: 174-176 (1996); Muenke et al., Am. J. Hum.Genet., 60: 555-564 (1997)) and Crouzon syndrome with acanthosisnigricans (Meyers et al., Nature Genetics, 11: 462-464 (1995)). Crouzonsyndrome is associated with specific point mutations in FGFR2 and bothfamilial and sporadic forms of Pfeiffer syndrome are associated withmutations in FGFR1 and FGFR2 (Galvin et al., PNAS USA, 93: 7894-7899(1996); Schell et al., Hum Mol Gen, 4: 323-328 (1995)). Mutations inFGFRs result in constitutive activation of the mutated receptors andincreased receptor protein tyrosine kinase activity, rendering cells andtissue unable to differentiate.

Specifically, the achondroplasia mutation results in enhanced stabilityof the mutated receptor, dissociating receptor activation fromdown-regulation, leading to restrained chondrocyte maturation and bonegrowth inhibition (reviewed in Vajo et al., Endocrine Reviews, 21(1):23-39 (2000)).

There is accumulating evidence for mutations activating FGFR3 in varioustypes of cancer.

Constitutively activated FGFR3 in two common epithelial cancers, bladderand cervix, as well as in multiple myeloma, is the first evidence of anoncogenic role for FGFR3 in carcinomas. In addition, a very recent studyreports the presence of FGFR3 activating mutations in a large proportionof benign skin tumors (Logie et al., Hum Mol Genet. 2005). FGFR3currently appears to be the most frequently mutated oncogene in bladdercancer where it is mutated in almost 50% of the total bladder cancercases and in about 70% of cases having superficial bladder tumors(Cappellen, et al., Nature Genetics 1999, 23; 19-20; van Rhijn, et al.,Cancer Research 2001, 61: 1265-1268; Billerey, et al, Am. J. Pathol.2001, 158:1955-1959, WO 2004/085676). FGFR3 aberrant overexpression as aconsequence of the chromosomal translocation t(4,14) is reported in10-25% of multiple myeloma cases (Chesi et al., Nature Genetics 1997,16: 260-264; Richelda et al., Blood 1997, 90: 4061-4070; Sibley et al.,BJH 2002, 118: 514-520; Santra et al., Blood 2003, 101: 2374-2476).FGFR3 activating mutations are seen in 5-10% of multiple myelomas witht(4,14) and are associated with tumor progression (Chesi et al., NatureGenetics 1997, 16: 260-264; Chesi et al., Blood, 97 (3): 729-736 (2001);Intini, et al, BJH 2001, 114: 362-364).

In this context, the consequences of FGFR3 signaling appear to be celltype-specific. In chondrocytes, FGFR3 hyperactivation results in growthinhibition (reviewed in Omitz, 2001), whereas in the myeloma cell itcontributes to tumor progression (Chesi et al., 2001).

The inhibition of FGFR3 activity has been found to represent a means fortreating T cell mediated inflammatory or autoimmune diseases, as forexample in treatment of T-cell mediated inflammatory or autoimmunediseases including but not limited to rheumatoid arthritis (RA),collagen II arthritis, multiple sclerosis (MS), systemic lupuserythematosus (SLE), psoriasis, juvenile onset diabetes, Sjogren'sdisease, thyroid disease, sarcoidosis, autoimmune uveitis, inflammatorybowel disease (Crohn's and ulcerative colitis), celiac disease andmyasthenia gravis. See WO 2004/110487.

Disorders resulting from FGFR3 mutations are described also in WO03/023004 and WO 02/102972.

Gene amplification and/or overexpression of FGFR1, FGFR2 and FGFR4 hasbeen implicated in breast cancer (Penault-Llorca et al., Int J Cancer1995; Theillet et al., Genes Chrom. Cancer 1993; Adnane et al., Oncogene1991; Jaakola et al., Int J Cancer 1993; Yamada et al., Neuro Res 2002).Overexpression of FGFR1 and FGFR4 is also associated with pancreaticadenocarcinomas and astrocytomas (Kobrin et al., Cancer Research 1993;Yamanaka et al., Cancer Research 1993; Shah et al., Oncogene 2002;Yamaguchi et al., PNAS 1994; Yamada et al., Neuro Res 2002). Prostatecancer has also been related to FGFR1 overexpression (Girl et al., ClinCancer Res 1999).

There is an unmet need for highly selective molecules capable ofblocking aberrant constitutive receptor protein tyrosine kinaseactivity, in particular FGFR activity, thereby addressing the clinicalmanifestations associated with the above-mentioned mutations, andmodulating various biological functions.

In view of the large number of protein kinase inhibitors and themultitude of proliferative and other PK-related diseases, there is anever-existing need to provide novel classes of compounds that are usefulas PK inhibitors and thus in the treatment of these Protein TyrosineKinase (PTK) related diseases. What is required are new classes ofpharmaceutically advantageous PK inhibiting compounds.

Epidermal Growth Factor Family and Related Diseases

The epidermal growth factor receptor (EGF-R) and ErbB-2 kinase areprotein tyrosine kinase receptors which, together with their familymembers ErbB-3 and ErbB-4, play a key role in signal transmission in alarge number of mammalian cells, including human cells, especiallyepithelial cells, cells of the immune system and cells of the centraland peripheral nervous system. For example, in various cell types,EGF-induced activation of receptor-associated protein tyrosine kinase isa prerequisite for cell division and hence for the proliferation of thecell population. Most importantly, overexpression of the EGF-R (HER-1)and/or ErbB-2 (HER-2) has been observed in substantial fractions of manyhuman tumours. EGF-R, e.g., was found to be overexpressed in nonsmall-cell lung cancers, squameous carcinoma (head and neck), breast,gastric, ovarian, colon and prostate cancers as well as in gliomas.ErbB-2 was found to be overexpressed in squameous carcinoma (head andneck), breast, gastric, and ovarian cancers as well as in gliomas.

Citation of any document herein is not intended as an admission thatsuch document is pertinent prior art, or considered material to thepatentability of any claim of the present application. Any statement asto content or a date of any document is based on the informationavailable to applicant at the time of filing and does not constitute anadmission as to the correctness of such a statement.

SUMMARY OF THE INVENTION

The present invention relates to compounds of Formula (I) and salts,esters, N-oxides or prodrugs thereof:

wheren is 0, 1, 2, 3, 4 or 5;X, Y and Z are each independently selected from N or C—R⁵, wherein atleast two of X, Y and Z are N; andX¹ is oxygen,R¹, R², R³ and R⁴ if present, are each independently selected from anorganic or inorganic moiety,

where the inorganic moiety is especially selected from halo, especiallychloro, hydroxyl, cyano, azo (N═N=N), nitro; and

where the organic moiety is substituted or unsubstituted and may beattached via a linker, -L¹-, the organic moiety being especiallyselected from hydrogen; lower aliphatic (especially C₁, C₂, C₃ or C₄aliphatic) e.g. lower alkyl, lower alkenyl, lower alkynyl; amino;guanidino; hydroxyguanidino; formamidino; isothioureido; ureido;mercapto; C(O)H or other acyl; acyloxy; substituted hydroxy; carboxy;sulfo; sulfamoyl; carbamoyl; a substituted or unsubstituted cyclicgroup, for example the cyclic group (whether substituted orunsubstituted) may be cycloalkyl, e.g. cyclohexyl, phenyl, pyrrole,imidazole, pyrazole, isoxazole, oxazole, thiazole, pyridazine,pyrimidine, pyrazine, pyridyl, indole, isoindole, indazole, purine,indolizidine, quinoline, isoquinoline, quinazoline, pteridine,quinolizidine, piperidyl, piperazinyl, pyrollidine, morpholinyl orthiomorpholinyl and, for example, substituted lower aliphatic orsubstituted hydroxy may be substituted by such substituted orunsubstituted cyclic groups.

-   -   and -L¹- having 1, 2, 3, 4 or 5 in-chain atoms (e.g. selected        from C, N, O and S) and optionally being selected from (i) C₁,        C₂, C₃ or C₄ alkyl, such an alkyl group optionally being        interrupted and/or terminated by    -   an —O—, —C(O)— or —NR^(a)— linkage; —O—; —S—; —C(O)—;        cyclopropyl (regarded as having two in-chain atoms) and        chemically appropriate combinations thereof; and —NR^(a)—,        wherein R^(a) is hydrogen, hydroxy, hydrocarbyloxy or        hydrocarbyl, wherein hydrocarbyl is optionally interrupted by an        —O— or —NH— linkage and may be, for example, selected from an        aliphatic group (e.g. having 1 to 7 carbon atoms, for example 1,        2, 3, or 4), cycloalkyl, especially cyclohexyl, cycloalkenyl,        especially cyclohexenyl, or another carbocyclic group, for        example phenyl; where the hydrocarbyl moiety is substituted or        unsubstituted;        each R⁴ is the same or different and selected from an organic or        inorganic moiety, for example, each R⁴ is the same or different        and selected from halogen; hydroxy; protected hydroxy for        example trialkylsilylhydroxy; amino; amidino; guanidino;        hydroxyguanidino; formamidino; isothioureido; ureido; mercapto;        C(O)H or other acyl; acyloxy; carboxy; sulfo; sulfamoyl;        carbamoyl; cyano; azo; nitro; C₁-C₇ aliphatic optionally        substituted by one or more halogens and/or one or two functional        groups selected from hydroxy, protected hydroxy for example        trialkylsilylhydroxy, amino, amidino, guanidino,        hydroxyguanidino, formamidino, isothioureido, ureido, mercapto,        C(O)H or other acyl, acyloxy, carboxy, sulfo, sulfamoyl,        carbamoyl, cyano, azo, or nitro; all of the aforesaid hydroxy,        amino, amidino, guanidino, hydroxyguanidino, formamidino,        isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl and        carbamoyl groups in turn optionally being substituted on at        least one heteroatom by one or more C₁-C₇ aliphatic groups.

In a particular embodiment, there is provided a compound of Formula (I),wherein:

n is 0, 1, 2, 3, 4 or 5;X, Y and Z are each independently selected from N or C—R⁵, wherein atleast two of X, Y and Z are N; andR¹, R² and R⁵ are each independently selected from H, R^(z)-L¹-;halogen; hydroxy; protected hydroxy for example trialkylsilylhydroxy;amino; amidino; guanidino; hydroxyguanidino; formamidino; isothioureido;ureido; mercapto; C(O)H or other acyl; acyloxy; carboxy; sulfo;sulfamoyl; carbamoyl; cyano; azo; nitro; C₁-C₇ aliphatic optionallysubstituted by one or more halogens and/or one or two functional groupsselected from hydroxy, protected hydroxy for exampletrialkylsilylhydroxy, amino, amidino, guanidino, hydroxyguanidino,formamidino, isothioureido, ureido, mercapto, C(O)H or other acyl,acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, or nitro; allof the aforesaid hydroxy, amino, amidino, guanidino, hydroxyguanidino,formamidino, isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyland carbamoyl groups in turn optionally being substituted on at leastone heteroatom by one or, where possible, more C₁-C₇ aliphatic groups,

-   -   wherein -L¹- has 1, 2, 3, 4 or 5 in-chain atoms and is selected        from        -   C₁, C₂, C₃ or C₄ aliphatic optionally interrupted and/or            terminated by a linkage selected from the group consisting            of —NR^(a)—; —O—; —S—; —C(O)—; cyclopropyl (regarded as            having two in-chain atoms) and chemically appropriate            combinations thereof;        -   —NR^(a)—; —O—; —S—; —C(O)—; cyclopropyl (regarded as having            two in-chain atoms) and chemically appropriate combinations            thereof; and        -   wherein R^(a) is hydrogen, hydroxy, hydrocarbyloxy or            hydrocarbyl, wherein hydrocarbyl has from 1 to 15 carbon            atoms, is optionally interrupted by an —O— or —NH— linkage            and is unsubstituted or is substituted by hydroxy, halo,            amino or mono- or di-(C₁-C₄)alkylamino, lower alkanoyl,            trifluoromethyl, cyano, azo or nitro;    -   and R^(z) is a moiety containing from 1 to 30 plural valent        atoms selected from C, N, O, S and Si as well as monovalent        atoms selected from H and halo;        R³ is H or a moiety containing from 1 to 30 plural valent atoms        selected from C, N, O, S and Si as well as monovalent atoms        selected from H and halo;        each R⁴ is the same or different and selected from halogen;        hydroxy; protected hydroxy for example trialkylsilylhydroxy;        amino; amidino; guanidino; hydroxyguanidino; formamidino;        isothioureido; ureido; mercapto; C(O)H or other acyl; acyloxy;        carboxy; sulfo; sulfamoyl; carbamoyl; cyano; azo; nitro; C₁-C₇        aliphatic optionally substituted by one or more halogens and/or        one or two functional groups selected from hydroxy, protected        hydroxy for example trialkylsilylhydroxy, amino, amidino,        guanidino, hydroxyguanidino, formamidino, isothioureido, ureido,        mercapto, C(O)H or other acyl, acyloxy, carboxy, sulfo,        sulfamoyl, carbamoyl, cyano, azo, or nitro; all of the aforesaid        hydroxy, amino, amidino, guanidino, hydroxyguanidino,        formamidino, isothioureido, ureido, mercapto, carboxy, sulfo,        sulfamoyl and carbamoyl groups in turn optionally being        substituted on at least one heteroatom by one or, where        possible, more C₁-C₇ aliphatic groups,        or pharmaceutically acceptable salts, esters, N-oxides or        prodrugs thereof.

Often, at least one of R¹, R² and R⁵ is not H; in exemplary compounds asingle one of R¹, R² and R⁵ is not H. Normally R¹ is not H. Theinvention includes amongst others compounds in which at least one of R¹,R² and R⁵ is R^(z)-L¹-. It includes a class of compounds in which asingle one of R¹, R² and R⁵ is R^(z)-L¹-, particularly R¹. The inventionincludes a class of compounds in which R² and R⁵ are H and R¹ is not H,e.g. is R^(z)-L¹-.

Chemically appropriate combinations of —NIR^(a)—; —O—; —S—; —C(O)—;cyclopropyl are combinations which form a chemically stable moiety, suchas —NR^(a)C(O)—; —C(O)NR^(a)—; —C(O)O— and —OC(O)—, for example. In manyclasses of compounds, L¹ does not comprise cyclopropyl.

It has now been found that the above compounds, which may be describedas belonging to the heteroaryl aryl urea class, show inhibition of anumber of protein tyrosine kinases.

It is believed that certain compound of formula (I) lack novelty per se.In one embodiment, therefore, the invention provides compounds offormula (I) and salts, esters, N-oxides or prodrugs thereof excludingcompounds of formula (I) in which:

(A) n is 0; R³ is H; Y and Z are N; X is N, C—SO₂(NH) or C—NO₂ (or in awider exclusionary embodiment any C—R⁵ group); R² is H, SCH₂CH═CH₂ orSMe; and R¹ is of the formula NR′R″ where R′ and R″ together with theiradjoining nitrogen form morpholino or one of R′ and R″ is H and theother is phenyl, phenyl substituted by a single substituent selectedfrom Me and Cl, or is —C(O)NHPh;(B) n is 1; R⁴ is methoxy; R³ is H; X is CH; Y and Z are N; R¹ is NH₂;and R² is H or SMe;(C) n is 1; R⁴ is Cl; R³ is ethyl; X, Y and Z are N; and one of R¹ andR² is H whilst the other is NEt₂; or(D) n is 2; one R⁴ is meta-Cl and the other is para-methyl, R³ is H; X,Y and Z are N; and one of R¹ and R² is H whilst the other is PhNH—,m-chloroPhNH—, p-chloroPhNH—, m-methylPhNH— or p-methylPhNH—.

In embodiments, there are additionally excluded (a) salts of theexcluded compounds, (b) esters of excluded compounds, (c) N-oxides ofexcluded compounds, (d) prodrugs of excluded compounds, or (e) 1, 2, 3or 4 of (a), (b), (c) and (d), e.g. all thereof.

Included in the invention is a method of treating a proteinkinase-dependent disease in a warm-blooded animal, for example a human,comprising administering to the animal a therapeutically effectiveamount of a compound of Formula I or a salt, ester, N-oxide or prodrugthereof.

Also included is the use of a compound of Formula I or a salt, ester,N-oxide or prodrug thereof for the manufacture of a medicament for usein the treatment of a protein kinase-dependent disease.

As another aspect of the invention may be mentioned oral pharmaceuticalformulations comprising compounds of Formula I or salts, esters,N-oxides or prodrugs thereof. Also to be mentioned as a further aspectare intravenous pharmaceutical formulations comprising compounds ofFormula I or salts, esters, N-oxides or prodrugs thereof.

In embodiments of the aforesaid method, use and formulations, thecompound is in the form of the compound of Formula (I) as such. In otherembodiments, the compound is in the form of a salt, ester, N-oxide orprodrug thereof. Thus, in certain embodiments the compound is in theform of a salt whilst in others it is not.

The compounds of Formula (I) (or exemplary formula thereof), describedbelow in more detail, especially show inhibition of protein kinases e.g.protein tyrosine kinases. As examples of kinases inhibited by thecompounds of the disclosure may be mentioned FGFR1, FGFR2, FGFR3 andFGFR4. Another inhibited kinase is the receptor tyrosine kinase VEGF-R,in particular the VEGF receptor KDR (VEGF-R2). The disclosed compoundsare appropriate for the inhibition of one or more of these and/or otherprotein tyrosine kinases and/or for the inhibition of mutants of theseenzymes. In view of these activities, the compounds can be used for thetreatment of diseases related to, especially, aberrant or excessiveactivity of such types of kinases, especially those mentioned.

The compounds of the disclosure can exist in different forms, such asfree acids, free bases, esters and other prodrugs, salts and tautomers,for example, and the disclosure includes all variant forms of thecompounds.

The extent of protection includes counterfeit or fraudulent productswhich contain or purport to contain a compound of the inventionirrespective of whether they do in fact contain such a compound andirrespective of whether any such compound is contained in atherapeutically effective amount. Included in the scope of protectiontherefore are packages which include a description or instructions whichindicate that the package contains a species or pharmaceuticalformulation or composition of the invention and a product which is orcomprises, or purports to be or comprise, such a formulation,composition or species.

Throughout the description and claims of this specification, thesingular encompasses the plural unless the context otherwise requires.In particular, where the indefinite article is used, the specificationis to be understood as contemplating plurality as well as singularity,unless the context requires otherwise.

Features, integers, characteristics, compounds, chemical moieties orgroups described in conjunction with a particular aspect, embodiment orexample of the invention are to be understood to be applicable to anyother aspect, embodiment or example described herein unless incompatibletherewith.

Throughout the description and claims of this specification, the words“comprise” and “contain” and variations of the words, for example“comprising” and “comprises”, mean “including but not limited to”, andare not intended to (and do not) exclude other moieties, additives,components, integers or steps.

Further aspects and embodiments of the disclosure are set forth in thefollowing description and claims.

DETAILED DESCRIPTION

The present invention relates to compounds of Formula I as describedabove and salts, esters, N-oxides or prodrugs thereof. In an aspect,therefore, the invention provides products which are compounds ofFormula I and salts, esters, N-oxides or prodrugs thereof.

In embodiments, the products do not include compounds which are believedto be included in the prior art and in which:

(A) n is 0; R³ is H; Y and Z are N; X is N, C—SO₂(NH) or C—NO₂ (or in awider exclusionary embodiment any C—R⁵ group); R² is H, SCH₂CH═CH₂ orSMe; and R¹ is of the formula NR′R″ where R′ and R″ together with theiradjoining nitrogen form morpholino or one of R′ and R″ is H and theother is phenyl, phenyl substituted by a single substituent selectedfrom Me and Cl, or is —C(O)NHPh;(B) n is 1; R⁴ is methoxy; R³ is H; X is CH; Y and Z are N; R¹ is NH₂;and R² is H or SMe;(C) n is 1; R⁴ is Cl; R³ is ethyl; X, Y and Z are N; and one of R¹ andR² is H whilst the other is NEt₂; or(D) n is 2; one R⁴ is meta-Cl and the other is para-methyl, R³ is H; X,Y and Z are N; and one of R¹ and R² is H whilst the other is PhNH—,m-chloroPhNH—, p-chloroPhNH—, m-methylPhNH— or p-methylPhNH—.

In another embodiment, 1, 2, 3 or 4 of excluded categories (A), (B), (C)and (D) is expanded to read as follows:

(A) n is 0; R³ is H; Y and Z are N; X is N or C—R⁵; R² is H or asubstituent; and R¹ is of the formula NR′R″ where R′ and R″ togetherwith the nitrogen form a substituted or unsubstituted ring or R′ and R″are each independently H or a substituent;(B) n is 1; R⁴ is a substituent; R³ is H; Y and Z are N; X is CH (or inother embodiments is C—R⁵); R² is H OR SMe (or in some excludedcompounds S substituted by any substituent); and R¹ is NH₂ (or in aclass of excluded compounds is substituted amino or—in someinstances—any substituent)(C) n is 1; R⁴ is halo or alkyl (or in a class of embodiments is anysubstituent); R³ is alkyl; X, Y and Z are N; and one of R¹ and R² is Hwhilst the other is a substituent; or(D) n is 2; each R⁴ is independently selected from halo and alkyl (or ina class of embodiments is any substituent); R³ is H; X, Y and Z are N;and one of R¹ and R² is H whilst the other is amino or substituted amino(or in an embodiment is any substituent).

In embodiments, there are additionally excluded (a) salts of theexcluded compounds, (b) esters of excluded compounds, (c) N-oxides ofexcluded compounds, (d) prodrugs of excluded compounds, or (e) 1, 2, 3or 4 of (a), (b), (c) and (d), e.g. all thereof.

Structural fragments and substituents of the compounds of Formula (I)will now be considered in turn:

The Left Hand Ring

By the “left hand ring” is meant the fragment:

In a class of compounds, two of X, Y and Z are N, and in one sub-class Xand Y are N while in another or X and Z are N; in an alternative classall of X, Y and Z are N. A particular class consists of compounds inwhich Y and Z are N, thus forming by way of example Fragment (A):

Substituent R⁵

Considering now the left hand ring without restriction, i.e. withoutlimitation to Fragment (A), the or each R⁵ may independently be an R¹group, for example as more particularly defined below, independently ofthe identity of R¹.

In some compounds the or each R⁵ is independently H; hydroxy; halo;amino or mono- or di-alkylamino; cyano; azo or nitro; an aliphatic grouphaving 1 to 7 carbon atoms and optionally interrupted by an —O— or —NH—linkage and/or linked to the left hand ring by a said linkage and/orsubstituted by hydroxy, halo, amino or mono- or di-alkylamino, cyano,azo or nitro; or acyl wherein the carbonyl moiety is substituted by asaid aliphatic group; hydroxy, amino, mono- or dialkylamino, cyano, azoor nitro. Alkyl groups may have for example 1 to 7, e.g. 1, 2, 3 or 4carbon atoms.

Often, R⁵ is H, halo, hydroxy, amino, mono- or dialkylamino, alkyl (e.g.methyl), alkyl interrupted by an —O— or —NH— linkage and/or linked tothe left hand ring by a said linkage (e.g. to form alkoxy, for examplemethoxy), trifluoromethyl, hydroxy, amino, mono- or dialkylamino; anyalkyl moiety (interrupted or not) typically has 1, 2, 3 or 4 carbonatoms.

In a class of compounds, R⁵ is H or halo, particularly H, F or Cl, forexample is H or F. In a particular class of compounds, the or each R⁵ isH.

The above description of R⁵ applies of course to Fragment (A) as much asto other left hand ring structures.

Substituent R²

Again considering the left hand ring without restriction, R² may be anymoiety described above in relation to R⁵ (e.g. may be any R¹ group asdescribed more particularly below) and of course R² and R⁵ may be thesame or different.

In some compounds, R² and the or each R⁵ are independently H; halo; analiphatic group (e.g. having 1 to 7 carbon atoms, for example 1, 2, 3,or 4), the aliphatic group optionally being interrupted by an —O— or—NH— linkage and/or linked to the left hand ring by a said linkageand/or substituted by hydroxy, halo, amino or mono- or di-alkylamino,acyl wherein the carbonyl moiety is substituted by a said aliphaticgroup, trifluoromethyl, hydroxy, amino, mono- or di-alkylamino, cyano,azo or nitro.

Often, both R² and the or each R⁵ are independently H, halo, alkyl,alkyl interrupted by an —O— or —NH— linkage and/or linked to the lefthand ring by a said linkage, trifluoromethyl, hydroxy, amino, mono- ordialkylamino; any alkyl moiety (interrupted or not) typically has 1, 2,3 or 4 carbon atoms.

In a class of compounds, both R² and the or each R⁵ are independently Hor halo, particularly H, F or Cl, for example are H or F. In aparticular class of compounds, R² and the or each R⁵ are H.

The above descriptions of R² and of R² and R⁵ apply of course toFragment (A) as much as to other left hand ring structures.

It will be understood from the aforegoing description that a particularleft hand ring structure is Fragment (B):

Substituent R¹

As previously described, R¹ is an organic or inorganic moiety.

As inorganic moieties may be mentioned halo, hydroxyl, amino, cyano, azo(N═N═N) and nitro. F and Clare exemplary halogens.

The organic moiety, designated R^(z), is substituted or unsubstitutedand may be attached via a linker, -L¹-, the organic moiety beingespecially selected from hydrogen; lower aliphatic (especially C₁, C₂,C₃ or C₄ aliphatic) e.g. lower alkyl, lower alkenyl, lower alkynyl;amino; guanidino; hydroxyguanidino; formamidino; isothioureido; ureido;mercapto; carboxy; sulfo; sulfamoyl; carbamoyl; C(O)H or other acyl;acyloxy; substituted hydroxy; a substituted or unsubstituted cyclicgroup, for example the cyclic group (whether substituted orunsubstituted) may be cycloalkyl, e.g. cyclohexyl, phenyl, pyrrole,imidazole, pyrazole, isoxazole, oxazole, thiazole, pyridazine,pyrimidine, pyrazine, pyridyl, indole, isoindole, indazole, purine,indolizidine, quinoline, isoquinoline, quinazoline, pteridine,quinolizidine, piperidyl, piperazinyl, pyrollidine, morpholinyl orthiomorpholinyl and, for example, substituted lower aliphatic orsubstituted hydroxy may be substituted by such substituted orunsubstituted cyclic groups. See below for a description of particularclasses of R^(z) moiety.

Linker -L¹- has 1, 2, 3, 4 or 5 in-chain atoms and is selected from C₁,C₂, C₃ or C₄ aliphatic (notably linear aliphatic, and aliphaticparticularly being alkyl) optionally interrupted and/or terminated by alinkage selected from the group consisting of —NR^(a)—; —O—; —S—;—C(O)—; cyclopropyl (regarded as having two in-chain atoms) andchemically appropriate combinations thereof; —NR^(a)—; —O—; —S—; —C(O)—;cyclopropyl (regarded as having two in-chain atoms) and chemicallyappropriate combinations thereof; and —NR^(a)—, wherein R^(a) ishydrogen, hydroxy, hydrocarbyloxy or hydrocarbyl, wherein hydrocarbylhas from 1 to 15 carbon atoms (e.g. 1 to 7), is optionally interruptedby an —O— or —NH— linkage and may be, for example, selected from analiphatic group (e.g. having 1 to 7 carbon atoms, for example 1, 2, 3,or 4, aliphatic particularly being alkyl), cycloalkyl, especiallycyclohexyl, cycloalkenyl, especially cyclohexenyl, or anothercarbocyclic group, for example phenyl; where the hydrocarbyl moiety issubstituted or unsubstituted. Exemplary substituents are hydroxy, halo,amino or mono- or di-(C₁-C₄)alkylamino, lower alkanoyl, trifluoromethyl,cyano, azo or nitro. W is particularly H.

In a class of compounds, R¹ includes a linker L¹; in a sub-class, thelinker is —NR^(a)—, alkyl terminated at the left hand ring by (i.ejoined to the left hand ring by) —NR^(a)—, alkyl terminated at its endremote from the left hand ring by —NR^(a)—, or alkyl interrupted by—NR^(a)— wherein alkyl has 1, 2, 3 or 4 carbon atoms. In this class ofcompounds, W is particularly H. A preferred linker is —NH—.

In other words, a common left hand ring structure is represented byFragment (C):

where R^(a) is as described above and preferably H, and R^(z) is asubstituted or unsubstituted organic moiety as mentioned above and asfurther described below. Also to be mentioned are compounds in whichR^(z) is H, i.e. in which R¹ is amino when R^(a) is also H, as well asvariants in which R¹ is another substituted or unsubstituted basicgroup, for example amidino, guanidino; hydroxyguanidino; formamidino;isothioureido or ureido.

As previously described, therefore, R¹ may in certain compounds comprisea substituted or unsubstituted organic moiety, optionally joined to theleft hand ring through a linker L¹. Thus, R¹ in such compounds may berepresented as R^(z)-L¹-, where R^(z) is a substituted or anunsubstituted organic moiety. This applies equally to left hand ringstructures which do not correspond to fragment (C) as to those which do.

R^(z) is commonly a moiety containing from 1 to 30 in-chain and/orin-ring atoms selected from C, N, O, S and Si and in which one or morehydrogens are optionally replaced by halogen. Alternatively stated, suchR^(z) groups have from 1 to 30 plural valent atoms selected from C, N,O, S and Si as well as monovalent atoms selected from H and halo, e.g.selected from H, F, Cl and Br, for example H, F and Cl. In some R^(z)moieties there are from 1 to 25 plural valent atoms, e.g. 1 to 20, suchas 1 to 16, for example.

Included are compounds in which R^(z) contains one or a combination ofmoieties selected from categories 1), 2) and 3) below and optionally oneor more moieties selected from category 4) below:

-   -   1) aliphatic moieties, in particular having from 1 to 7 carbon        atoms, e.g. 1, 2, 3 or 4, particularly alkyl or alkenyl        moieties, e.g. alkyl;    -   2) carbocyclic rings, which may be saturated or unsaturated        (e.g. aromatic), particularly to be mentioned are bicyclic and        monocyclic rings and especially monocyclic rings having 5 or 6        ring members;    -   3) heterocyclic rings, which may be saturated or unsaturated        (e.g. aromatic), particularly to be mentioned are bicyclic and        monocyclic rings and especially monocyclic rings having 5 or 6        ring members;    -   4) linking moieties selected from O, N, Si and C(O), wherein two        or more linking moieties may be combined to form a larger        linking group for example C(O)O, C(O)NH or OC(O)NH.

In these compounds, a plurality of moieties selected from 1), 2) and 3)may be linked together either directly or through a linking moiety 4).Of course, one compound may contain one or more linking moieties. Tri-or more valent linking moieties such as N and Si may serve to linktogether just two moieties selected from 1), 2) and 3), in which casethe remaining valencies are suitably occupied by hydrogen; alternativelyN or Si may link together three said moieties, or Si may link togetherfour said moieties. Where R^(z) contains a plurality of moietiesselected from 1), 2) and 3), the moieties may be the same of differentand may independently be selected from categories 1), 2) and 3).

Moieties 1), 2) and 3) may be substituted by one or more substituentsselected from, in particular, hydroxy, amino, amidino, guanidino,hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, C(O)H orother lower acyl, lower acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl,cyano, azo, or nitro, which hydroxy, amino, amidino, guanidino,hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, carboxy,sulfo, sulfamoyl, carbamoyl and cyano groups are in turn optionallysubstituted on at least one heteroatom by one or, where possible, moreC₁-C₇ aliphatic groups. Often, but not always, R^(z) has 0, 1, 2, 3, or4 such substituents; sometimes there are a larger number of substituentsas can happen, for example, when Fe contains one or more perfluorinatedalkyl or cyclic groups, e.g. CF₃, as well as other optionalsubstituents.

Particular moieties 1), 2) and 3) to mention are straight chain andbranched alkyl, 5- and 6-membered carbocyclic rings (notably phenyl andcyclohexyl), and 5- and 6-membered heterocyclic rings (notably5-membered rings containing a single heteroatom, e.g. furan, thiophene,pyrrole; and 6-membered rings containing one or two heteroatoms, e.g.piperidine, piperazine, morpholine, pyridine, pyrimidine and pyrazine).

The invention includes compounds of Formula (I) wherein R¹ is of theformula R^(z)—NR^(a)—, as described above, and R^(z) is selected from

(i) C₁-C₇ aliphatic moities,(ii) C₁-C₇ aliphatic substituted by one or more halogens and/or one ortwo functional groups selected from hydroxy, amino, amidino, guanidino,hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, C(O)H orother lower acyl, lower acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl,cyano, azo, or nitro, which hydroxy, amino, amidino, guanidino,hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, carboxy,sulfo, sulfamoyl, carbamoyl and cyano groups are in turn optionallysubstituted on at least one heteroatom by one or, where possible, moreC₁-C₇ aliphatic groups,(iii) a group of the formula

-   -   where:    -   ring A represents a mono- or bi-cyclic ring, particularly a 5-        or 6-membered carbocyclic or heterocyclic ring;    -   m is 0, 1, 2; 3, 4 or 5, e.g. 0, 1 or 2;    -   the or each R^(b) is independently selected from        -L²-NR^(c)R^(d); -L²-RING where RING is a mono- or bi-cyclic        ring, particularly a 5- or 6-membered carbocyclic or        heterocyclic ring, optionally substituted as defined below;        halogen; hydroxy; protected hydroxy for example        trialkylsilylhydroxy; amino; amidino; guanidino;        hydroxyguanidino; formamidino; isothioureido; ureido; mercapto;        C(O)H or other lower acyl; lower acyloxy; carboxy; sulfo;        sulfamoyl; carbamoyl; cyano; azo; or nitro; and C₁-C₇ aliphatic        optionally substituted by one or more halogens and/or one or two        functional groups selected from hydroxy, protected hydroxy for        example trialkylsilylhydroxy, amino, amidino, guanidino,        hydroxyguanidino, formamidino, isothioureido, ureido, mercapto,        C(O)H or other lower acyl, lower acyloxy, carboxy, sulfo,        sulfamoyl, carbamoyl, cyano, azo, or nitro; all of which        hydroxy, amino, amidino, guanidino, hydroxyguanidino,        formamidino, isothioureido, ureido, mercapto, carboxy, sulfo,        sulfamoyl, carbamoyl and cyano groups are in turn optionally        substituted on at least one heteroatom by one or, where        possible, more C₁-C₇ aliphatic groups,    -   wherein L² is a direct bond; a linkage selected    -   from —O—; —S—; —C(O)—; —OC(O)—; —NR^(a)C(O)—; —C(O)—NR^(a)—;        —OC(O)—NR^(a)—; cyclopropyl and —NR^(a)—; or is a C₁-C₇        aliphatic group optionally interrupted and/or terminated at a        single end or at both ends by a said linkage (R^(a) being as        previously defined and typically H);    -   and wherein R^(c) and R^(d) are each independently selected from        hydrogen, and C₁-C₇ aliphatic optionally substituted by one or        more halogens, by an optionally substituted 5- or 6-membered        heterocyclic or carbocyclic ring, and/or one or two functional        groups selected from hydroxy, protected hydroxy for example        trialkylsilylhydroxy, amino, amidino, guanidino,        hydroxyguanidino, formamidino, isothioureido, ureido, mercapto,        C(O)H or other lower acyl, lower acyloxy, carboxy, sulfo,        sulfamoyl, carbamoyl, cyano, azo, or nitro, which hydroxy,        amino, amidino, guanidino, hydroxyguanidino, formamidino,        isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl,        carbamoyl and cyano groups are in turn optionally substituted on        at least one heteroatom by one or more C₁-C₇ aliphatic groups,    -   or R^(c) and R^(d) together with their adjoining nitrogen form a        5- or 6-membered ring optionally substituted as described below,        said optionally substituted rings independently of each other        being substituted by 0, 1, 2, 3, 4 or 5 substituents selected        from halogen; hydroxy; protected hydroxy for example        trialkylsilylhydroxy; amino; amidino; guanidino;        hydroxyguanidino; formamidino; isothioureido; ureido; mercapto;        C(O)H or other lower acyl; lower acyloxy; carboxy; sulfo;        sulfamoyl; carbamoyl; cyano; azo; nitro; C₁-C₇ aliphatic        optionally substituted by one or more halogens and/or one or two        functional groups selected from hydroxy, protected hydroxy for        example trialkylsilylhydroxy, amino, amidino, guanidino,        hydroxyguanidino, formamidino, isothioureido, ureido, mercapto,        C(O)H or other lower acyl; lower acyloxy carboxy, sulfo,        sulfamoyl, carbamoyl, cyano, azo, or nitro; all of the aforesaid        hydroxy, amino, amidino, guanidino, hydroxyguanidino,        formamidino, isothioureido, ureido, mercapto, carboxy, sulfo,        sulfamoyl and carbamoyl groups in turn optionally being        substituted on at least one heteroatom by one or, where        possible, more C₁-C₇ aliphatic groups (for example, therefore, a        ring may be substituted by an alkoxy group, e.g. methoxy or        ethoxy).

Still considering compounds wherein R¹ is of the formula R^(z)—NR^(a)—and R^(z) is selected from categories (i), (ii) and (iii) above,aliphatic often has 1, 2, 3 or 4 carbon atoms and is often linear, butsometimes branched. In a class of compounds, aliphatic is alkyl, e.g.linear or branched alkyl having 1, 2, 3 or 4 carbon atoms; linear alkylis more common, irrespective of the number of carbon atoms.

In a sub-class of those compounds wherein R¹ is of the formulaR^(z)—NR^(a)—, R^(z) is alkyl, e.g. linear or branched alkyl having 1,2, 3 or 4 carbon atoms; linear alkyl being more common, irrespective ofthe number of carbon atoms. As already described, there also includedcompounds in which R^(z) is H. This sub-class therefore comprisescompounds in which R¹ is amino or mono- or di-alkylamino.

Turning now to those compounds in which R^(z) is a category (iii) group,i.e. is of the formula

ring A is typically a 6-membered carbocyclic or heterocyclic ring,particularly phenyl, cyclohexyl or cyclohexenyl. Of these, phenyl ispreferred. In other instances, ring A is a 5-membered carbocyclic orheterocyclic ring. Other exemplary residues forming ring A are pyridyland pyrimidyl.

Integer m may be 0.

Integer m is often 1. Where m is greater than one, all the R^(b) groupsor all the R^(b) groups except one are often halogen (notably F or Cl),methyl or trifluoromethyl. Also to be mentioned in this regard arehydroxy and amino. Often, a single R^(b) group is selected from-L²-NR^(c)R^(d) and -L²-RING and there are 0, 1 or 2 additionalsubstituents which are not -L²-NR^(c)R^(d) or -L²-RING but are, forexample, halogen (notably F or Cl), lower alkyl (e.g. methyl), loweralkoxy (e.g. methoxy), hydroxy, amino or trifluoromethyl.

Accordingly, the invention includes compounds in which R^(z) is, e.g. a6-membered carbocyclic ring (notably phenyl) substituted by 1, 2, 3, 4or 5 halogens, e.g. selected from F, Cl and Br; typically, such phenylrings are mono- or di-substituted, e.g. are 2- and/or 4-substituted by For 3-substituted by Cl. In some cases of plural substitution by halogen,all the halogens are the same. Thus, in a class of compounds R^(z) is amonocyclic ring, particularly a 6-membered carbocyclic ring (notablyphenyl), substituted solely by one or more halogens, particularlyselected from F and Cl; sometimes the or each halogen is F but in someother cases the or each halogen is Cl.

In another class of compounds, R^(z) is a monocyclic ring, particularlya 6-membered carbocyclic ring (notably phenyl), substituted by 1, 2, 3,4 or 5 substituents, e.g. 1 or 2 substituents, selected from alkyl,alkoxy, alkanoyl, alkanoyloxy, haloalkyl, amino, mono- or di-alkylamino,cyano, halogen, hydroxy or protected hydroxy, wherein alkyl or the alkylpart of alkoxy and alkanoyl(oxy) has 1, 2, 3 or 4 carbon atoms;exemplary substituents in this case are methyl, ethyl, methoxy, ethoxy,acetyl, trifluoromethyl, cyano, F, Cl and OH. Certain such rings have 0,1 or 2 substituents, e.g. 0 or 1.

In one class of compounds, L² is a direct bond, linear alkyl, linearalkyl terminated adjacent ring A by a said linkage, or is a saidlinkage. In a sub-class, any said linkage is —O— or —C(O)—, of which —O—may be particularly mentioned.

The invention includes a class of compounds in which ring A is a6-membered ring, particularly phenyl, cyclohexyl or cyclohexenyl and hasone or two substituents R^(b) independently selected from-L²-NR^(c)R^(d) and -L²-RING, as defined previously. In a sub-class,there is a single substituent at, in particular, the 3-position or4-position selected from -L²-NR^(c)R^(d) and -L²-RING such that the lefthand ring has a structure corresponding to Fragments (D1), (D2), (E1) or(E2):

As previously described, R^(a) is commonly H. Also as previouslydescribed, the phenyl ring may be replaced by cyclohexyl orcyclohexenyl, particularly cyclohexyl. It may alternatively be replacedby a 5- or 6-membered heterocycle, particularly pyridine.

In some embodiments, the phenyl ring of the above fragments (or otherring replacing phenyl) has 1, 2, 3 or 4 further substituents, forexample selected from halogen (notably F or Cl), methyl, methoxy ortrifluoromethyl, e.g. 1 or 2 such substituents. Also to be mentioned inthis regard are hydroxy and amino.

L² is as previously described, that is a direct bond; a linkage selectedfrom —O—; —S—; —C(O)—; —OC(O)—; —NR^(a)C(O)—; —C(O)—NR^(a)—;—OC(O)—NR^(a)—; cyclopropyl and —NR^(a)—; or C₁-C₇ aliphatic optionallyinterrupted and/or terminated at a single end or at both ends by a saidlinkage (R² being as previously defined and typically H). Any aliphaticmoiety is often alkyl, e.g. alkyl or other aliphatic having 1, 2, 3 or 4carbon atoms, as in the case of a sub-class of linkers L² in whichaliphatic moieties are methyl, ethyl or n-propyl.

In particular fragments (D) and (E), L² is a direct bond, linear alkyl,linear alkyl terminated adjacent the phenyl ring in the aboverepresentations of the fragments by a said linkage, or is a saidlinkage; suitably but not necessarily any said linkage is —O— or —C(O)—,of which —O— may be particularly mentioned. Thus, the above fragments(D) and (E) may comprise sub-fragments -Ph-NR^(c)R^(d), -Ph-RING,-Ph-O-alkyl-NR^(c)R^(d), -Ph-alkyl-NR^(c)R^(d), -Ph-alkyl-RIN G, andalso to be mentioned are sub-fragments -Ph-O—NR^(c)R^(d), -Ph-O-RING,-Ph-C(O)—NR¹R^(d) and -Ph-C(O)—RING, where, in all these sub-fragmentswhich contain alkyl, alkyl may be e.g. methyl, ethyl or n-propyl, orn-butyl.

Considering now in more detail fragments (D1) and (D2), these contain amoiety RING which is a cyclic moiety and in many cases a 5- or6-membered carbocyclic or heterocyclic ring optionally substituted asdefined previously. Exemplary rings are saturated, e.g. cyclopentane orcyclohexane. In particular compounds, RING is a 5- or 6-memberedheterocycle, often containing one or two heteroatoms, typically selectedfrom O and N; in a sub-class, the heterocycles contain one or twonitrogens and, where there is a single nitrogen, optionally an oxygen.Particular heterocycles include a nitrogen which is not a member of adouble bond and these are more particularly saturated heterocycles. Asheterocycles may be mentioned pyrrolidine, piperidine, piperazine andmorpholine; in some compounds, RING is piperidine having its nitrogen atthe 4-position relative to L². As already described, RING may besubstituted and, in one class of compounds, is substituted by 0, 1, 2,3, 4 or 5 substituents, e.g. selected from C₁-C₇ aliphatic groups,optionally substituted as described above, and less frequently C₁-C₇aliphatic-oxy of which the aliphatic group is optionally substituted asdescribed above. Any aliphatic group is often alkyl (straight chain orbranched), e.g. alkyl or other aliphatic having 1, 2, 3 or 4 carbonatoms, as in the case of a sub-class of fragments (D1) and (D2) havingsubstituents which are methyl, ethyl or n-propyl. Exemplary substituentson RING include straight chain or branched C₁, C₂, C₃ or O₄ alkyl suchas, e.g., methyl, ethyl n-propyl, isopropyl or t-butyl, of which methylmay be particularly mentioned, halogen (notably F or Cl) and C₁, C₂, C₃or C₄ alkoxy; also to be mentioned are hydroxy and amino. Alkyl moietiesmay be unsubstituted or substituted, e.g. by halogen (notably F or Cl)or in some cases by hydroxy or amino.

In some classes of RING moieties, there are 0, 1, 2, 3, 4 or 5 suchsubstituents selected from alkyl, alkoxy, alkanoyl, alkanoyloxy,haloalkyl, amino, mono- or di-alkylamino, cyano, halogen, hydroxy orprotected hydroxy, wherein alkyl or the alkyl part of alkoxy andalkanoyl(oxy) has 1, 2, 3 or 4 carbon atoms; exemplary substituents inthis case are methyl, ethyl, methoxy, ethoxy, acetyl, trifluoromethyl,cyano, F, Cl and OH. Certain RING moieties have 0, 1 or 2 substituents,e.g. 0 or 1.

Considering now in more detail fragments (E1) and (E2), these contain amoiety NR^(c)R^(d). R^(c) and R^(d) are as previously described. In oneclass of these fragments, R^(c) and R^(d) are the same or different (butmore usually the same) and selected from C₁-C₇, e.g. C₁-C₄ aliphaticgroups, optionally substituted as described above. As aliphatic R^(c)and R^(d) moieties may be mentioned alkyl, e.g having 1, 2, 3 or 4carbon atoms, as in the case of a sub-class of fragments (E1) and (E2)having substituents which are methyl, ethyl or n-propyl. Alkyl or otheraliphatic moieties may be substituted e.g. by amino or mono- or di(C₁-C₄) alkylamino, or e.g. by a 5- or 6-membered heterocyclic orcarbocyclic ring optionally substituted as previously described, or beunsubstituted. Thus, particular L²NR^(c)R^(d) moieties are —OCH₂NMe₂,—OCH₂NEt₂, —OCH₂CH₂NMe₂, —OCH₂CH₂NEt₂, —OCH₂CH₂CH₂NMe₂, —OCH₂CH₂CH₂NEt₂, —CH₂NMe₂, —CH₂NEt₂, —CH₂CH₂NMe₂, —CH₂CH₂NEt₂, —CH₂CH₂CH₂NMe₂,and —CH₂CH₂CH₂NEt₂.

In another class of fragments (E1) and (E2), R^(c) and R^(d) togetherwith the adjoining nitrogen form a heterocyclic moiety (normally a 5- or6-membered heterocyclic ring), optionally substituted as previouslydescribed. In addition to the nitrogen of moiety NR^(c)R^(d), theheterocyclic ring may contain at least one further heteroatom, and oftenexactly one further heteroatom, in either case typically selected from Oand N; in a sub-class, the heterocycles contain altogether one or twonitrogens and, where there is a single nitrogen, optionally an oxygen.Particular heterocycles include a nitrogen which is not a member of adouble bond and these are more particularly saturated heterocycles. Asheterocycles may be mentioned pyrrolidine, piperidine, piperazine andmorpholine; of these particular heterocycles are piperazine andmorpholine. As already described, the heterocycle may be substitutedand, in one class of compounds, is substituted by 0, 1, 2, 3, 4 or 5substituents, e.g. selected from C₁-C₇ aliphatic groups, optionallysubstituted as described above, and less frequently C₁-C₇ aliphatic-oxyof which the aliphatic group is optionally substituted as describedabove. Any aliphatic group is often alkyl (straight chain or branched),e.g. alkyl or other aliphatic having 1, 2, 3 or 4 carbon atoms, as inthe case of a sub-class of cyclic (E1) and (E2) fragments havingsubstituents which are methyl, ethyl or n-propyl. Exemplary substituentson cyclic (E1) and (E2) fragments include straight chain or branched C₁,C₂, C₃ or C₄ alkyl such as, e.g., methyl, ethyl n-propyl, isopropyl ort-butyl, of which methyl may be particularly mentioned, halogen (notablyF or Cl) and C₁, C₂, C₃ or C₄ alkoxy; also to be mentioned are hydroxyand amino. Alkyl moieties may be unsubstituted or substituted, e.g. byhalogen (notably F or Cl) or in some cases by hydroxy or amino.

In some classes of cyclic (E1) and (E2) fragments (that is to sayfragments in which R^(c) and R^(d) together with the adjoining nitrogenform a ring), there are 0, 1, 2, 3, 4 or 5 such substituents selectedfrom alkyl, alkoxy, alkanoyl, alkanoyloxy, haloalkyl, amino, mono- ordi-alkylamino, cyano, halogen, hydroxy or protected hydroxy, whereinalkyl or the alkyl part of alkoxy and alkanoyl(oxy) has 1, 2, 3 or 4carbon atoms; exemplary substituents in this case are methyl, ethyl,methoxy, ethoxy, acetyl, trifluoromethyl, cyano, F, Cl and OH. Certaincyclic fragments have 0, 1 or 2 substituents, e.g. 0 or 1.

Particular L²NR^(c)R^(d) moieties are -Pip, -Morph, —OCH₂Pip,—OCH₂-Morph, —OCH₂CH₂Pip, —OCH₂CH₂-Morph, —OCH₂CH₂CH₂Pip,—OCH₂CH₂CH₂-Morph, —CH₂Pip, —CH₂-Morph, —CH₂CH₂Pip, —CH₂CH₂-Morph,—CH₂CH₂CH₂Pip, and —CH₂CH₂CH₂-Morph. Also to be mentioned are —C(O)Pipand —C(O)Morph. The abbreviation “Pip” stands for piperazine and “Morph”for morpholine, and these rings may be substituted as previouslydescribed. In particular piperazine is optionally N-substituted.piperazine and morpholine may be substituted by a C₁-C₇ aliphatic groupas mentioned in the previous paragraph, for example a straight chain orbranched C₁, C₂, C₃ or C₄ moiety selected from alkyl and haloalkyl suchas, e.g., methyl, trifluoromethyl, ethyl n-propyl, isopropyl or t-butyl,of which methyl and trifluoromethyl are exemplary. As described before,R^(a) is in particular hydrogen.

Amongst the classes of compounds which are particularly to be mentionedare those in which the left hand ring has a structure corresponding toFragment (D1) or (E1). Particularly exemplary are such compounds havinga fragment (E1) in which R^(c) and R^(d) together with the adjoiningnitrogen form a 5- or 6-membered heterocyclic ring as described above.These rings may be substituted as previously described. In particularthey are optionally N-substituted by a C₁-C₇ aliphatic group asmentioned earlier, for example a straight chain or branched C₁, C₂, C₃or C₄ moiety selected from alkyl and haloalkyl such as, e.g., methyl,trifluoromethyl, ethyl n-propyl, isopropyl or t-butyl, of which methyland trifluoromethyl are exemplary. As described before, R^(a) is inparticular hydrogen.

It will be appreciated from the aforegoing that the invention includescompounds having a left hand ring having the structure of the followingFragment (F):

where L²NR^(c)R^(d) is in particular -Pip, -Morph, —OCH₂Pip,—OCH₂-Morph, —OCH₂CH₂Pip, —OCH₂CH₂-Morph, —OCH₂CH₂CH₂Pip,—OCH₂CH₂CH₂-Morph, —CH₂Pip, —CH₂-Morph, —CH₂CH₂Pip, —CH₂CH₂-Morph,—CH₂CH₂CH₂Pip, and —CH₂CH₂CH₂-Morph, or is —C(O)Pip or —C(O)Morph. “Pip”and “Morph” are as described in the last but one paragraph.

Substituent R³

Substituent R³ is as previously described in relation to Formula (I).

In embodiments, R³ is selected from H, R^(b) groups, and categories (i),(ii) and (iii) described above in relation to R^(z), independently ofthe identity of R^(z). In one class of embodiments, R³ is H or a C₁-C₇aliphatic group, for example straight chain or branched C₁-C₄ alkyl suchas, e.g., methyl, ethyl or n-propyl, of which methyl is exemplary. Inother compounds, R³ is a C₁-C₇ aliphatic group (for example straightchain or branched C₁-C₄ alkyl such as, e.g., methyl, ethyl or n-propyl)substituted by a mono- or bi-cyclic ring, particularly a 5- or6-membered saturated or unsaturated carbocyclic or heterocyclic ring,for example by phenyl, pyrrolidine, piperidine, piperazine, morpholine,thiophene, furan, pyrrole, pyridine, pyrazine or pyran. R³ may thereforebe straight chain alkyl (or other straight chain aliphatic group, forexample in either case having up to 4 carbon atoms) substituted at itsfree end by such a mono- or bi-cyclic ring.

In one class of compounds R³ is a category (iii) moiety, that is, amoiety having the structure:

as previously described. The identity of R³ is independent of that ofR^(z), as already stated.

However, as particular compounds, may be mentioned those in which justone of R^(z) and R³ is a category (iii) moiety. In a subclass, one ofR^(z) and R³ is a category (iii) moiety and the other is H; to bementioned in this regard are compounds in which R³ is a category (iii)moiety and R¹ is NH₂, or alternatively mono- or di-alkyl amino.

Where R³ is a category (iii) moiety, it may have a structurecorresponding to the category (iii) structures found in Fragments (D1),(D2), (E1), (E2) or (F), as previously described.

The Right Hand Ring

By the “right hand ring” is meant the fragment:

It has previously been mentioned that n is 0, 1, 2, 3, 4 or 5 and thateach R⁴ is the same or different and selected from an organic orinorganic moiety, for example, each R⁴ is the same or different andselected from halogen; hydroxy; protected hydroxy for exampletrialkylsilylhydroxy; amino; amidino; guanidino; hydroxyguanidino;formamidino; isothioureido; ureido; mercapto; C(O)H or other acyl;acyloxy; carboxy; sulfo; sulfamoyl; carbamoyl; cyano; azo; nitro; C₁-C₇aliphatic optionally substituted by one or more halogens and/or one ortwo functional groups selected from hydroxy, protected hydroxy forexample trialkylsilylhydroxy, amino, amidino, guanidino,hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, C(O)H orother acyl, acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo,or nitro; all of the aforesaid hydroxy, amino, amidino, guanidino,hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, carboxy,sulfo, sulfamoyl and carbamoyl groups in turn optionally beingsubstituted on at least one heteroatom by one or, where possible, moreC₁-C₇ aliphatic groups (for example, therefore, R⁴ ring may be an alkoxygroup, e.g. methoxy or ethoxy).

Integer n is more usually 1, 2, 3 or 4, e.g. 2, 3 or 4. In particular,there are often R⁴ groups substituted at both ortho-positions andoptionally at least one or two other positions, e.g. there may be asingle further meta or para substituent.

R⁴ is particularly selected from hydroxy, protected hydroxy, loweralkoxy, lower alkyl, trifluoromethyl and halo, notably F or Cl. R⁴ mayalso be Br. Alkyl and the alkyl part of alkoxy may be branched or, moreusually, straight chain, and often have 1, 2, 3, or 4 carbon atoms, asfor example in the case of methyl, ethyl, methoxy and ethoxy. R⁴ isespecially selected from Cl, F, hydroxy, methyl, methoxy andtrifluoromethyl, e.g. is selected from Cl, F, methyl, methoxy andtrifluoromethyl, as in those compounds where R⁴ is Cl, F, methyl ormethoxy. In some of the compounds mentioned in this paragraph, chlorineis the sole halogen, in some others fluorine is the sole halogen. Thereader is reminded that, where there are plural R⁴ groups, they may bethe same or different.

Included are compounds in which there is halogen selected from F and Clat one or both ortho positions.

To be mentioned are right hand rings corresponding to Fragment (G):

where:

-   -   Q is selected from F and Cl;    -   U is selected from H, F, Cl, methyl, trifluoromethyl and        methoxy, and particularly Q and U are the same or different and        both selected from F and Cl;    -   T and V are the same or different and selected from H, methyl,        trifluoromethyl and methoxy, e.g. from H, methyl and methoxy.

In some Fragments (G), all of U, T and V are H. In other Fragments (G),Q and U are the same and selected from F and Cl.

A particular right hand ring is Fragment (H):

To be mentioned are right hand rings corresponding to Fragment (I):

-   -   where:    -   Q is selected from F and Cl;    -   U^(a) and U^(b) are each independently selected from H, F, Cl,        methyl, trifluoromethyl and methoxy; in some compounds U^(a) and        U^(b) are the same.

In exemplary Fragment (I) structures, all of Q, U^(a) and U^(b) are thesame and are fluorine or more particularly chlorine. In other exemplarystructures, Q is F or, particularly, Cl whilst U^(a) and U^(b) are thesame or different and selected from methyl, trifluoromethyl and methoxy;both U^(a) and U^(b) may be the same, e.g both may be methoxy.

The Compounds of Formula (I)

It has been described above how the compounds of formula (I) have thefollowing variable domains:

-   -   left hand ring    -   R³    -   right hand ring.

Various particular moieties have been described for each of thesevariable domains and it will be appreciated that any combination of suchmoieties is permissible.

To be mentioned are compounds having the following combinations, amongstmany others:

Left hand ring R³ Right hand ring Fragment (A) H, C₁-C₄ alkyl or C₁-C₄alkyl n = 1, 2, 3, or 4. substituted by an optionally R⁴ = selected fromCl, F, substituted 5- or 6- hydroxy, methyl, methoxy membered ring andtrifluoromethyl. Fragment (B) H, C₁-C₄ alkyl or C₁-C₄ alkyl n = 1, 2, 3,or 4. substituted by an optionally R⁴ = selected from Cl, F, substituted5- or 6- hydroxy, methyl, methoxy membered ring and trifluoromethyl.Fragment (C) H, C₁-C₄ alkyl or C₁-C₄ alkyl n = 1, 2, 3, or 4.substituted by an optionally R⁴ = selected from Cl, F, substituted 5- or6- hydroxy, methyl, methoxy membered ring and trifluoromethyl. Fragment(C), R^(a) = H, H, C₁-C₄ alkyl or C₁-C₄ alkyl n = 1, 2, 3, or 4. Rz =category (i) or (ii) substituted by an optionally R⁴ = selected from Cl,F, substituted 5- or 6- hydroxy, methyl, methoxy membered ring andtrifluoromethyl. Fragment (C), R^(a) = H, Category (iii) moiety, e.g. n= 1, 2, 3, or 4. Rz = category (i) or (ii) having a structure R⁴ =selected from Cl, F, corresponding to the hydroxy, methyl, methoxycategory (iii) structure of and trifluoromethyl. Fragment (D1) Fragment(C), R^(a) = H, Category (iii) moiety, e.g. n = 1, 2, 3, or 4. Rz =category (i) or (ii) having a structure R⁴ = selected from Cl, F,corresponding to the hydroxy, methyl, methoxy category (iii) structureof and trifluoromethyl. Fragment (D2) Fragment (C), R^(a) = H, Category(iii) moiety, e.g. n = 1, 2, 3, or 4. Rz = category (i) or (ii) having astructure R⁴ = selected from Cl, F, corresponding to the hydroxy,methyl, methoxy category (iii) structure of and trifluoromethyl.Fragment (E1). Fragment (C), R^(a) = H, Category (iii) moiety, e.g. n =1, 2, 3, or 4. Rz = category (i) or (ii) having a structure R⁴ =selected from Cl, F, corresponding to the hydroxy, methyl, methoxycategory (iii) structure of and trifluoromethyl. Fragment (E2). Fragment(C), R^(a) = H, Category (iii) moiety, e.g. n = 1, 2, 3, or 4. Rz =category (i) or (ii) having a structure R⁴ = selected from Cl, F,corresponding to the hydroxy, methyl, methoxy category (iii) structureof and trifluoromethyl. Fragment (F). Fragment (C), R^(a) = H, C₁-C₄alkyl or C₁-C₄ alkyl n = 1, 2, 3, or 4. R^(z) = category (iii)substituted by an optionally R⁴ = selected from Cl, F, substituted 5- or6- hydroxy, methyl, methoxy membered ring and trifluoromethyl. Fragment(D1) C₁-C₄ alkyl or C₁-C₄ alkyl n = 1, 2, 3, or 4. substituted by anoptionally R⁴ = selected from Cl, F, substituted 5- or 6- hydroxy,methyl, methoxy membered ring and trifluoromethyl. Fragment (D2) C₁-C₄alkyl or C₁-C₄ alkyl n = 1, 2, 3, or 4. substituted by an optionally R⁴= selected from Cl, F, substituted 5- or 6- hydroxy, methyl, methoxymembered ring and trifluoromethyl. Fragment (E1) C₁-C₄ alkyl or C₁-C₄alkyl n = 1, 2, 3, or 4. substituted by an optionally R⁴ = selected fromCl, F, substituted 5- or 6- hydroxy, methyl, methoxy membered ring andtrifluoromethyl. Fragment (E2) C₁-C₄ alkyl or C₁-C₄ alkyl n = 1, 2, 3,or 4. substituted by an optionally R⁴ = selected from Cl, F, substituted5- or 6- hydroxy, methyl, methoxy membered ring and trifluoromethyl.Fragment (F) C₁-C₄ alkyl or C₁-C₄ alkyl n = 1, 2, 3, or 4. substitutedby an optionally R⁴ = selected from Cl, F, substituted 5- or 6- hydroxy,methyl, methoxy membered ring and trifluoromethyl. Fragment (C), R^(a) Hn = 1, 2, 3, or 4. typically = H, R^(z) = category (iii) R⁴ = selectedfrom Cl, F, hydroxy, methyl, methoxy and trifluoromethyl. Fragment (D1);R^(a) H n = 1, 2, 3, or 4. typically = H, R⁴ = selected from Cl, F,hydroxy, methyl, methoxy and trifluoromethyl. Fragment (D2); R^(a) H n =1, 2, 3, or 4. typically = H, R⁴ = selected from Cl, F, hydroxy, methyl,methoxy and trifluoromethyl. Fragment (E1); R^(a) H n = 1, 2, 3, or 4.typically = H, R⁴ = selected from Cl, F, hydroxy, methyl, methoxy andtrifluoromethyl. Fragment (E2); R^(a) H n = 1, 2, 3, or 4. typically =H, R⁴ = selected from Cl, F, hydroxy, methyl, methoxy andtrifluoromethyl. Fragment (F) H n = 1, 2, 3, or 4. R⁴ = selected fromCl, F, hydroxy, methyl, methoxy and trifluoromethyl. Fragment (A) H,C₁-C₄ alkyl or C₁-C₄ alkyl R⁴ is Fragment substituted by an optionally(G), (H) or (I). substituted 5- or 6- membered ring Fragment (B) H,C₁-C₄ alkyl or C₁-C₄ alkyl R⁴ is Fragment substituted by an optionally(G), (H) or (I). substituted 5- or 6- membered ring Fragment (C) H,C₁-C₄ alkyl or C₁-C₄ alkyl R⁴ is Fragment substituted by an optionally(G), (H) or (I). substituted 5- or 6- membered ring Fragment (C), R^(a)= H, H, C₁-C₄ alkyl or C₁-C₄ alkyl R⁴ is Fragment Rz = category (i) or(ii) substituted by an optionally (G), (H) or (I). substituted 5- or 6-membered ring Fragment (C), R^(a) = H, Category (iii) moiety, e.g. R⁴ isFragment Rz = category (i) or (ii) having a structure (G), (H) or (I).corresponding to the category (iii) structure of Fragment (D1) Fragment(C), R^(a) = H, Category (iii) moiety, e.g. R⁴ is Fragment Rz = category(i) or (ii) having a structure (G), (H) or (I). corresponding to thecategory (iii) structure of Fragment (D2) Fragment (C), R^(a) = H,Category (iii) moiety, e.g. R⁴ is Fragment Rz = category (i) or (ii)having a structure (G), (H) or (I). corresponding to the category (iii)structure of Fragment (E1). Fragment (C), R^(a) = H, Category (iii)moiety, e.g. R⁴ is Fragment Rz = category (i) or (ii) having a structure(G), (H) or (I). corresponding to the category (iii) structure ofFragment (E2). Fragment (C), R^(a) = H, Category (iii) moiety, e.g. R⁴is Fragment Rz = category (i) or (ii) having a structure (G), (H) or(I). corresponding to the category (iii) structure of Fragment (F).Fragment (C), R^(a) = H, C₁-C₄ alkyl or C₁-C₄ alkyl R⁴ is Fragment R^(z)= category (iii) substituted by an optionally (G), (H) or (I).substituted 5- or 6- membered ring Fragment (D1) C₁-C₄ alkyl or C₁-C₄alkyl R⁴ is Fragment substituted by an optionally (G), (H) or (I).substituted 5- or 6- membered ring Fragment (D2) C₁-C₄ alkyl or C₁-C₄alkyl R⁴ is Fragment substituted by an optionally (G), (H) or (I).substituted 5- or 6- membered ring Fragment (E1) C₁-C₄ alkyl or C₁-C₄alkyl R⁴ is Fragment substituted by an optionally (G), (H) or (I).substituted 5- or 6- membered ring Fragment (E2) C₁-C₄ alkyl or C₁-C₄alkyl R⁴ is Fragment substituted by an optionally (G), (H) or (I).substituted 5- or 6- membered ring Fragment (F) C₁-C₄ alkyl or C₁-C₄alkyl R⁴ is Fragment substituted by an optionally (G), (H) or (I).substituted 5- or 6- membered ring Fragment (C), R^(a) H R⁴ is Fragmenttypically = H, R^(z) = category (iii) (G), (H) or (I). Fragment (D1);R^(a) H R⁴ is Fragment typically = H, (G), (H) or (I). Fragment (D2);R^(a) H R⁴ is Fragment typically = H, (G), (H) or (I). Fragment (E1);R^(a) H R⁴ is Fragment typically = H, (G), (H) or (I). Fragment (E2);R^(a) H R⁴ is Fragment typically = H, (G), (H) or (I). Fragment (F) H R⁴is Fragment (G), (H) or (I).

When R³ is an optionally substituted ring, substituents are as describedpreviously, e.g. methyl, ethyl, methoxy, trifluoromethyl, amino orhydroxy.

Each row of the above table provides support for an individual patentclaim, presented by itself or with one or more other claims, eachcorresponding to a respective row of the table. The previous textprovides support for claims dependent on such claims in describingsub-classes of the respective features or feature combinations of eachrow. For each row in the Table, a patent claim or claims may be writtento protect individually a sub-class or sub-classes of the subject matterrepresented by the row.

It will be understood from the aforegoing that a sub-set of theCompounds of Formula (I) are of the following Formulae (II) and (III):

In Formulae (II) and (III), it is often the case that two of X, Y and Zare N and that R⁵ and R² are H, e.g. in many compounds X is CH, Y and Zare N and R² is H. Alternatively, all of X, Y and Z are N and R² is H.Ring A is typically phenyl or a wholly or partially hydrogenatedanalogue thereof. Alternatively it may be a heterocycle, typically ofsix members, e.g. pyridine or pyrimidine. Integer m may be 0, 1 or 2,e.g. 1. In some cases there are one or more R^(b) moieties which are For Cl, as previously described, e.g. the only R^(b) moieties may be oneor two moieties selected from F and Cl.

Accordingly, Formulae (II) and (III) encompass the followingsub-classes, amongst others:

-   -   1) Two of X, Y and Z are N, R⁵ and R² are H, ring A is phenyl or        a wholly or partially hydrogenated analogue thereof, m is 0, 1        or 2, e.g. 1;    -   2) Two of X, Y and Z are N, R⁵ and R² are H, ring A is a        heterocycle, typically of six members, e.g. pyridine or        pyrimidine, m is 0, 1 or 2, e.g. 1;    -   3) All of X, Y and Z are N, R² is H, ring A is phenyl or a        wholly or partially hydrogenated analogue thereof, m is 0, 1 or        2, e.g. 1;    -   4) All of X, Y and Z are N, R² is H, ring A is a heterocycle,        typically of six members, e.g. pyridine or pyrimidine, m is 0, 1        or 2, e.g. 1;    -   5) X is CH, Y and Z are N, R² is H, ring A is phenyl or a wholly        or partially hydrogenated analogue thereof, m is 0, 1 or 2, e.g.        1;    -   6) X is CH, Y and Z are N, R² is H, ring A is a heterocycle,        typically of six members, e.g. pyridine or pyrimidine, m is 0, 1        or 2, e.g. 1.

In some instances of sub-classes 1), 2), 3) 4), 5) and 6) there are oneor more R^(b) moieties which are F or Cl, as previously described, e.g.the only R^(b) moieties may be one or two moieties selected from F andCl.

More commonly, ring A is substituted by one or two R^(b) moieties (andnormally a single R^(b) moiety) comprising -L²-RING or -L²-NR^(c)R^(d),and optionally other substituents (e.g. numbering 1, 2 or 3) selectedfrom e.g. halogen; hydroxy; protected hydroxy for exampletrialkylsilylhydroxy; amino; amidino; guanidino; hydroxyguanidino;formamidino; isothioureido; ureido; mercapto; C(O)H or other lower acyl;lower acyloxy; carboxy; sulfo; sulfamoyl; carbamoyl; cyano; azo; nitro;which substituents are in turn optionally substituted on at least oneheteroatom by one or, where possible, more C₁, C₂, C₃ or C₄ alkylgroups. Particular additional substituents on ring A are halogen, loweralkyl (e.g. methyl), lower alkoxy (e.g. methoxy), hydroxy, amino ortrifluoromethyl.

Also to be mentioned therefore are compounds of the following formulae(IV), (V), (VI) and (VII):

where

-   -   L²NR^(c)R^(d) is in particular -Pip, -Morph, —OCH₂Pip,        —OCH₂-Morph, —OCH₂CH₂Pip, —OCH₂CH₂-Morph, —OCH₂CH₂CH₂Pip,        —OCH₂CH₂CH₂-Morph, —CH₂Pip, —CH₂-Morph, —CH₂CH₂Pip,        —CH₂CH₂-Morph, —CH₂CH₂CH₂Pip, and —CH₂CH₂CH₂-Morph, or is        —C(O)Pip or —C(O)Morph (or of course these heterocycles are        replaced by another described herein, or in other embodiments        R^(c) and R^(d) form a non-cyclic structure as previously        described);    -   L²RING is in particular -RING, —OCH₂RING, —OCH₂CH₂RING,        —OCH₂CH₂CH₂RING, —CH₂RING, —CH₂CH₂RING, —CH₂CH₂CH₂RING, or is        —C(O)RING, where RING is in particular pyrrolidine, piperidine,        piperazine or morpholine, or it may be another RING moiety        disclosed herein;    -   R³ is as previously described and is particularly but not        necessarily H;    -   R⁴ is as previously described and is particularly but not        necessarily selected from Cl, F, hydroxy, methyl, methoxy and        trifluoromethyl;    -   n is 0, 1, 2, 3, 4 or 5, e.g. is 1, 2, 3, or 4.

In embodiments, RING or a heterocycle formed by L²NR^(c)R^(d) issubstituted by 1, 2, 3, 4 or 5 substituents, e.g. 1 or 2 substituents,selected from alkyl, alkoxy, alkanoyl, alkanoyloxy, haloalkyl, amino,mono- or di-alkylamino, cyano, halogen, hydroxy or protected hydroxy,wherein alkyl or the alkyl part of alkoxy and alkanoyl(oxy) has 1, 2, 3or 4 carbon atoms; exemplary substituents in this case are methyl,ethyl, methoxy, ethoxy, acetyl, trifluoromethyl, cyano, F, Cl and OH.N-alkyl substituted piperazine or piperadine are exemplary, as are RINGmoieties as a class substituted by one or two substituents or more,selected from alkyl and haloalkyl (e.g. trifluoromethyl). As analternative to substitution, there may be no substitution.

Another embodiment comprises compounds of formula (XX):

where R^(zl) and R^(z2) are selected from hydrogen and straight chain orbranched alkyl having 1, 2, 3 or 4 carbon atoms, e.g. methyl or ethyl.In embodiments, one of R^(z1) and R^(z2) is hydrogen and moreparticularly both are hydrogen. It is often the case that X is CH, Y andZ are N and R² is H. Particular classes of compounds are of formulae(XXI), (XXII), (XXIII) and (XXIV):

where R^(z1) and R^(z2) are selected from hydrogen and straight chain orbranched alkyl having 1, 2, 3 or 4 carbon atoms, e.g. methyl or ethyl,and L²NR^(c)R^(d), L²RING, R³ and R⁴ are as described in relation toformulae (IV)-(VII).

The invention includes classes of compounds which correspond to Formulae(IV), (V), (VI), (VII), (XXI), (XXII), (XXIII) and (XXIV) in which thepyrimidine ring is replaced by a triazine ring

One embodiment of the present invention relates to compounds to Formula(I*), which represent a subgroup of the compounds of Formula I, andsalts, esters, N-oxides or prodrugs thereof:

in which compounds of Formula (I*) the radicals and symbols have thefollowing meaning:g is 0, 1, 2, 3, 4 or 5;n is 0, 1, 2, 3 or 4;X, Y and Z are each independently selected from N or C—R¹⁵, wherein atleast one of X, Y and Z is N;X¹ is oxygen,L¹ is a linker;RING* A is a mono- or bicyclic ring; andR¹, R², R³, R¹⁵ and R¹⁶, if present, are each independently selectedfrom an organic or inorganic moiety,

-   -   where the inorganic moiety is especially selected from halo,        especially chloro, hydroxyl, cyano, azo (N═N═N), nitro; and    -   where the organic moiety is substituted or unsubstituted and may        be attached via a linker, -L²-, the organic moiety being        especially selected from hydrogen; lower aliphatic (especially        C₁, C₂, C₃ or C₄ aliphatic) e.g. lower alkyl, lower alkenyl,        lower alkynyl; amino; guanidino; hydroxyguanidino; formamidino;        isothioureido; ureido; mercapto; C(O)H or other acyl; acyloxy;        substituted hydroxy; carboxy; sulfo; sulfamoyl; carbamoyl; a        substituted or unsubstituted cyclic group, for example the        cyclic group (whether substituted or unsubstituted) may be        cycloalkyl, e.g. cyclohexyl, phenyl, pyrrole, imidazole,        pyrazole, isoxazole, oxazole, thiazole, pyridazine, pyrimidine,        pyrazine, pyridyl, indole, isoindole, indazole, purine,        indolizidine, quinoline, isoquinoline, quinazoline, pteridine,        quinolizidine, piperidyl, piperazinyl, pyrollidine, morpholinyl        or thiomorpholinyl and, for example, substituted lower aliphatic        or substituted hydroxy may be substituted by such substituted or        unsubstituted cyclic groups,        L¹ and L² each independently being selected from moieties having        1, 2, 3, 4 or 5 in-chain atoms (e.g. selected from C, N, O        and S) and optionally being selected from (i) C₁, C₂, C₃ or C₄        alkyl, such an alkyl group optionally being interrupted and/or        terminated by an —O—, —C(O)— or —NR^(a)— linkage; —O—; —S—;        —C(O)—; cyclopropyl (regarded as having two in-chain atoms) and        chemically appropriate combinations thereof; and —NR^(a)—,        wherein R^(a) is hydrogen, hydroxy, hydrocarbyloxy or        hydrocarbyl, wherein hydrocarbyl is optionally interrupted by an        —O— or —NH— linkage and may be, for example, selected from an        aliphatic group (e.g. having 1 to 7 carbon atoms, for example 1,        2, 3, or 4), cycloalkyl, especially cyclohexyl, cycloalkenyl,        especially cyclohexenyl, or another carbocyclic group, for        example phenyl; where the hydrocarbyl moiety is substituted or        unsubstituted;        each R⁴ is the same or different and selected from an organic or        inorganic moiety, for example, each R⁴ is the same or different        and selected from halogen; hydroxy; protected hydroxy for        example trialkylsilylhydroxy; amino; amidino; guanidino;        hydroxyguanidino; formamidino; isothioureido; ureido; mercapto;        C(O)H or other acyl; acyloxy; carboxy; sulfo; sulfamoyl;        carbamoyl; cyano; azo; nitro; C₁-C₇ aliphatic optionally        substituted by one or more halogens and/or one or two functional        groups selected from hydroxy, protected hydroxy for example        trialkylsilylhydroxy, amino, amidino, guanidino,        hydroxyguanidino, formamidino, isothioureido, ureido, mercapto,        C(O)H or other acyl, acyloxy, carboxy, sulfo, sulfamoyl,        carbamoyl, cyano, azo, or nitro; all of the aforesaid hydroxy,        amino, amidino, guanidino, hydroxyguanidino, formamidino,        isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl and        carbamoyl groups in turn optionally being substituted on at        least one heteroatom by one or more C₁-C₇ aliphatic groups.

The disclosure concerning pharmaceutical compositions, dosages,combinations, pharmacological assays etc provided for the compounds ofFormula I apply to the compounds of Formula I* accordingly.

Chemically appropriate combinations of —NR^(a)—; —O—; —S—; —C(O)—;cyclopropyl are combinations which form a chemically stable moiety, suchas —NR^(a)C(O)—; —C(O)NR^(a)—; —C(O)O— and —OC(O)—, for example. In manyclasses of compounds, L¹ does not comprise cyclopropyl.

L¹ is in particular selected from —NR^(a)CO— and —CONR^(a)—.

In another particular embodiment, there is provided a compound ofFormula (II*):

wherein L¹¹ is selected from —NR^(a)CO— and —CONR^(a)— and the othersymbols are as defined in relation to Formula (I*).

Often, at least one of R¹, R² and R¹⁶ is not H; in exemplary compounds asingle one of R¹, R² and R¹⁶ is not H. Normally R¹ is not H. Theinvention includes amongst others compounds in which at least one of R¹,R² and R¹⁶ is Rz*-L³-. It includes a class of compounds in which asingle one of R¹, R² and R¹⁶ is Rz*-L³-, particularly R¹. The inventionincludes a class of compounds in which R² and R¹⁶ are H and R¹ is not H,e.g. is Rz*-L³- where L³ may be as hereinbefore defined for L¹.

In particular, the present invention pertains to compounsd of formula I*wherein

(a) all of X, Y and Z are N, (b) one of X, Y and Z is N,

(c) two or three of X and Y are N, or(d) both of X and Z are N.

The compounds of Formula I* and II* are in particular useful to treatAML via inhibition of the tyrosine kinase domain of Flt-3. A furtherembodiment of the present invention is a method of treating acutemyeloid leukemia (AML) which comprises administering a therapeuticallyeffective amount of a claimed compound.

The Raf serine/threonine kinases are essential components of theRas/Mitogen-Activated Protein Kinase (MAPK) signaling module thatcontrols a complex transcriptional program in response to externalcellular stimuli. Raf genes code for highly conservedserine-threonine-specific protein kinases which are known to bind to theras oncogene. They are part of a signal transduction pathway believed toconsist of receptor tyrosine kinases, p21 ras, Raf protein kinases, Mek1(ERK activator or MAPKK) kinases and ERK (MAPK) kinases, whichultimately phosphorylate transcription factors. In this pathway Rafkinases are activated by Ras and phosphorylate and activate two isoformsof Mitogen-Activated Protein Kinase Kinase (called Mek1 and Mek2), thatare dual specificity threonine/tyrosine kinases. Both Mek isoformsactivate Mitogen Activated Kinases 1 and 2 (MAPK, also calledExtracellular Ligand Regulated Kinase 1 and 2 or Erk1 and Erk2). TheMAPKs phosphorylate many substrates including transcription factors andin so doing set up their transcriptional program. Raf kinaseparticipation in the Ras/MAPK pathway influences and regulates manycellular functions such as proliferation, differentiation, survival,oncogenic transformation and apoptosis.

Both the essential role and the position of Raf in many signalingpathways have been demonstrated from studies using deregulated anddominant inhibitory Raf mutants in mammalian cells as well as fromstudies employing biochemical and genetic techniques model organisms. Inmany cases, the activation of Raf by receptors that stimulate cellulartyrosine phosphorylation is dependent on the activity of Ras, indicatingthat Ras functions upstream of Raf. Upon activation, Raf-1 thenphosphorylates and activates Mek1, resulting in the propagation of thesignal to downstream effectors, such as MAPK (mitogen-activated proteinkinase) (Crews et al. (1993) Cell 74:215). The Raf serine/threoninekinases are considered to be the primary Ras effectors involved in theproliferation of animal cells (Avruch et al. (1994) Trends Biochem. Sci.19:279).

Raf kinase has three distinct isoforms, Raf-1 (c-Raf), A-Raf, and B-Raf,distinguished by their ability to interact with Ras, to activate MAPKkinase pathway, tissue distribution and sub-cellular localization(Manias et al., Biochem. J. 351: 289-305, 2000; Weber et. al., Oncogene19:169-176, 2000; Pritchard et al., Mol. Cell. Biol. 15:6430-6442,1995).

Recent studies have shown that B-Raf mutation in the skin nevi is acritical step in the initiation of melanocytic neoplasia (Pollock et.al., Nature Genetics 25: 1-2, 2002). Furthermore, most recent studieshave emerged that activating mutation in the kinase domain of B-Rafoccurs in .about.66% of melanomas, 12% of colon carcinoma and 14% ofliver cancer (Davies et. al., Nature 417:949-954, 2002) (Yuen et. al.,Cancer Research 62:6451-6455, 2002) (Brose et. al., Cancer Research62:6997-7000, 2002).

Inhibitors of Raf/MEK/ERK pathway at the level of Raf kinases canpotentially be effective as therapeutic agents against tumors withover-expressed or mutated receptor tyrosine kinases, activatedintracellular tyrosine kinases, tumors with aberrantly expressed Grb2(an adapter protein that allows stimulation of Ras by the Sos exchangefactor) as well as tumors harboring activating mutations of Raf itself.In early clinical trails an inhibitor of Raf-1 kinase, that alsoinhibits B-Raf, has shown promise as a therapeutic agent in cancertherapy (Crump, Current Pharmaceutical Design 8: 2243-2248, 2002;Sebastien et. al., Current Pharmaceutical Design 8: 2249-2253, 2002).

Disruption of Raf expression in cell lines through the application ofRNA antisense technology has been shown to suppress both Ras andRaf-mediated tumorigenicity (Kolch et al., Nature 349:416-428, 1991;Monia et al., Nature Medicine 2(6):668-675, 1996).

As examples of kinases inhibited by the compounds of the disclosure maybe mentioned c-Abl and Bcr-Abl, in particular, inhibition of Bcr-Abl maybe mentioned. Another inhibited kinase is the receptor tyrosine kinaseVEGF-R, in particular the VEGF receptor KDR (VEGF-R2). The compounds ofthe present invention also inhibit mutant forms of the Bcr-Abl kinases.The disclosed compounds are appropriate for the inhibition of one ormore of these and/or other protein tyrosine kinases and/or thenon-receptor tyrosine kinase Raf, and/or for the inhibition of mutantsof these enzymes. In view of these activities, the compounds can be usedfor the treatment of diseases related to, especially, aberrant orexcessive activity of such types of kinases, especially those mentioned.

For example, as inhibitors of VEGF-receptor tyrosine kinase activity,the compounds of the invention may primarily inhibit the growth of bloodvessels and are thus, for example, effective against a number ofdiseases associated with deregulated angiogenesis, especially diseasescaused by ocular neovascularisation, especially retinopathies, such asdiabetic retinopathy or age-related macula degeneration, psoriasis,haemangioblastoma, such as haemangioma, mesangial cell proliferativedisorders, such as chronic or acute renal diseases, e.g. diabeticnephropathy, malignant nephrosclerosis, thrombotic microangiopathysyndromes or transplant rejection, or especially inflammatory renaldisease, such as glomerulonephritis, especially mesangioproliferativeglomerulonephritis, haemolytic-uraemic syndrome, diabetic nephropathy,hypertensive nephrosclerosis, atheroma, arterial restenosis, autoimmunediseases, diabetes, endometriosis, chronic asthma, and especiallyneoplastic diseases (solid tumors, but also leukemias and other “liquidtumors”, especially those expressing c-kit, KDR, Flt-1 or Flt-3), suchas especially breast cancer, cancer of the colon, lung cancer(especially small-cell lung cancer), cancer of the prostate or Kaposi'ssarcoma. A compound of Formula I*, II*, III*, IV*, V*, VI*, VII*, VIII*or IX* (or exemplary formula thereof) (or an N-oxide thereof) inhibitsthe growth of tumours and is especially suited to preventing themetastatic spread of tumors and the growth of micrometastases.

One class of target kinases of the compounds of the present inventionare Bcr-Abl mutants. The mutants Glu255→Lysine, Glu255→Valine or theThr315→Isoleucine may be especially mentioned, most especially theThr315→Isoleucine mutant.

Other Bcr-Abl mutants include Met244→NaI, Phe317→Leu, Leu248→Val,Met343→Thr, Gly250→Ala, Met351→Thr, Phe358→Ala, Gln252→Arg, Phe359→NaI,Tyr253→His, Val379→Ile, Tyr253→Phe, Phe382→Leu, Glu255→Lys, Leu387→Met,Glu255→NaI, His396→Pro, Phe311→Ile, His396→Arg, Phe311→Leu, Ser417→Tyr,Thr315→Ile, Glu459→Lys and Phe486→Ser.

Structural fragments and substituents of the compounds of Formula (I*)will now be considered in turn:

The Left Hand Ring

By the “left hand ring” is meant the fragment:

In a class of compounds, two of X, Y and Z are N, and in one sub-class Xand Y are N while in another or X and Z are N; in an alternative classat of X, Y and Z are N. A particular class consists of compounds inwhich Y and Z are N, thus forming by way of example Fragment (A*):

Substituent R¹⁵

Considering now the left hand ring without restriction, i.e. withoutlimitation to Fragment (A*), the or each R¹⁵ may independently be an R¹group, for example as more particularly defined below, independently ofthe identity of R¹.

In some compounds the or each R¹⁵ is independently H; hydroxy; halo;amino or mono- or di-alkylamino; cyano; azo or nitro; an aliphatic grouphaving 1 to 7 carbon atoms and optionally interrupted by an —O— or —NH—linkage and/or linked to the left hand ring by a said linkage and/orsubstituted by hydroxy, halo, amino or mono- or di-alkylamino, cyano,azo or nitro; or acyl wherein the carbonyl moiety is substituted by asaid aliphatic group; hydroxy, amino, mono- or dialkylamino, cyano, azoor nitro. Alkyl groups may have for example 1 to 7, e.g. 1, 2, 3 or 4carbon atoms.

Often, R¹⁵ is H, halo, hydroxy, amino, mono- or dialkylamino, alkyl(e.g. methyl), alkyl interrupted by an —O— or —NH— linkage and/or linkedto the left hand ring by a said linkage (e.g. to form alkoxy, forexample methoxy), trifluoromethyl, hydroxy, amino, mono- ordialkylamino; any alkyl moiety (interrupted or not) typically has 1, 2,3 or 4 carbon atoms.

In a class of compounds, R¹⁵ is H or halo, particularly H, F or Cl, forexample is H or F. In a particular class of compounds, the or each R¹⁵is H.

The above description of R¹⁵ applies of course to Fragment (A*) as muchas to other left hand ring structures.

Substituent R²

Again considering the left hand ring without restriction, R² may be anymoiety described above in relation to R¹⁵ (e.g. may be any R¹ group asdescribed more particularly below) and of course R² and R¹⁵ may be thesame or different.

In some compounds, R² and the or each R¹⁵ are independently H; halo; analiphatic group (e.g. having 1 to 7 carbon atoms, for example 1, 2, 3,or 4), the aliphatic group optionally being interrupted by an —O— or—NH— linkage and/or linked to the left hand ring by a said linkageand/or substituted by hydroxy, halo, amino or mono- or di-alkylamino,acyl wherein the carbonyl moiety is substituted by a said aliphaticgroup, trifluoromethyl, hydroxy, amino, mono- or di-alkylamino, cyano,azo or nitro.

Often, both R² and the or each R¹⁵ are independently H, halo, alkyl,alkyl interrupted by an —O— or —NH— linkage and/or linked to the lefthand ring by a said linkage, trifluoromethyl, hydroxy, amino, mono- ordialkylamino; any alkyl moiety (interrupted or not) typically has 1, 2,3 or 4 carbon atoms.

In a class of compounds, both R² and the or each R¹⁵ are independently Hor halo, particularly H, F or Cl, for example are H or F. In aparticular class of compounds, R² and the or each R¹⁵ are H.

The above descriptions of R² and of R² and R¹⁵ apply of course toFragment (A*) as much as to other left hand ring structures.

It will be understood from the aforegoing description that a particularleft hand ring structure is Fragment (B*):

Substituent R¹

As previously described, R¹ is an organic or inorganic moiety.

As inorganic moieties may be mentioned halo, hydroxyl, amino, cyano, azo(N═N═N) and nitro. F and Clare exemplary halogens.

-   -   The organic moiety, designated Rz*, is substituted or        unsubstituted and may be attached via a linker, -L³-, the        organic moiety being especially selected from hydrogen;    -   lower aliphatic (especially C₁, C₂, C₃ or C₄ aliphatic) e.g.        lower alkyl, lower alkenyl, lower alkynyl, particularly lower        and especially C₁, C₂, C₃ or C₄ alkyl;    -   substituted or unsubstituted functional groups selected from        amino; guanidino; hydroxyguanidino; formamidino; isothioureido;        ureido; mercapto; carboxy; sulfo; and hydroxy, exemplary        substituents being a protecting group, a said lower aliphatic        group, acyl particularly lower alkanoyl e.g. of which the alkyl        part has 1, 2, 3 or 4 carbon atoms, carboxy, esterified carboxy        (e.g. esterified by a said lower aliphatic group);    -   sulfamoyl; carbamoyl; C(O)H or other acyl; acyloxy; where acyl        is particularly lower alkanoyl e.g. of which the alkyl part has        1, 2, 3 or 4 carbon atoms;    -   substituted or unsubstituted cyclic groups, for example the        cyclic group (whether substituted or unsubstituted) may be        cycloalkyl, e.g. cyclohexyl, phenyl, pyrrole, imidazole,        pyrazole, isoxazole, oxazole, thiazole, pyridazine, pyrimidine,        pyrazine, pyridyl, indole, isoindole, indazole, purine,        indolizidine, quinoline, isoquinoline, quinazoline, pteridine,        quinolizidine, piperidyl, piperazinyl, pyrollidine, morpholinyl        or thiomorpholinyl and, for example, substituted lower aliphatic        or substituted hydroxy may be substituted by such substituted or        unsubstituted cyclic groups. See below for a description of        particular classes of Rz* moiety.

Linker -L³- has 1, 2, 3, 4 or 5 in-chain atoms and is selected from C1,C2, C3 or C4 aliphatic (notably linear aliphatic, and aliphaticparticularly being alkyl) optionally interrupted and/or terminated by alinkage selected from the group consisting of —NR^(a)—; —O—; —S—;—C(O)—; cyclopropyl (regarded as having two in-chain atoms) andchemically appropriate combinations thereof; —NR^(a)—; —O—; —S—; —C(O)—;cyclopropyl (regarded as having two in-chain atoms) and chemicallyappropriate combinations thereof; and —NR^(a)—, wherein R^(a) ishydrogen, hydroxy, hydrocarbyloxy or hydrocarbyl, wherein hydrocarbylhas from 1 to 15 carbon atoms (e.g. 1 to 7), is optionally interruptedby an —O— or —NH— linkage and may be, for example, selected from analiphatic group (e.g. having 1 to 7 carbon atoms, for example 1, 2, 3,or 4, aliphatic particularly being alkyl), cycloalkyl, especiallycyclohexyl, cycloalkenyl, especially cyclohexenyl, or anothercarbocyclic group, for example phenyl; where the hydrocarbyl moiety issubstituted or unsubstituted. Exemplary substituents are hydroxy, halo,amino or mono- or di-(C₁-C₄)alkylamino, lower alkanoyl, trifluoromethyl,cyano, azo or nitro. R^(a) is particularly H.

In a class of compounds, R¹ includes a linker L³; in a sub-class, thelinker is —NR^(a)—, alkyl terminated at the left hand ring by (i.ejoined to the left hand ring by) —NR^(a)—, alkyl terminated at its endremote from the left hand ring by —NR^(a)—, or alkyl interrupted by—NR^(a)— wherein alkyl has 1, 2, 3 or 4 carbon atoms. In this class ofcompounds, R^(a) is particularly H. A preferred linker is —NH—.

In other words, a common left hand ring structure is represented byFragment (C*):

where R^(a) is as described above and preferably H, and Rz* is asubstituted or unsubstituted organic moiety as mentioned above and asfurther described below. Also to be mentioned are compounds in which Rz*is H, i.e. in which R¹ is amino when R^(a) is also H, as well asvariants in which R¹ is another substituted or unsubstituted basicgroup, for example amidino, guanidino; hydroxyguanidino; formamidino;isothioureido or ureido.

As previously described, therefore, R¹ may in certain compounds comprisea substituted or unsubstituted organic moiety, optionally joined to theleft hand ring through a linker L³. Thus, R¹ in such compounds may berepresented as Rz*-L³-, where Rz* is a substituted or an unsubstitutedorganic moiety. This applies equally to left hand ring structures whichdo not correspond to Fragment (C*) as to those which do.

Rz* is commonly a moiety containing from 1 to 30 in-chain and/or in-ringatoms selected from C, N, O, S and Si and in which one or more hydrogensare optionally replaced by halogen. Alternatively stated, such Rz*groups have from 1 to 30 plural valent atoms selected from C, N, O, Sand Si as well as monovalent atoms selected from H and halo, e.g.selected from H, F, Cl and Br, for example H, F and Cl. In some Rz*moieties there are from 1 to 25 plural valent atoms, e.g. 1 to 20, suchas 1 to 16, for example.

Included are compounds in which Rz* contains one or a combination ofmoieties selected from categories 1), 2) and 3) below and optionally oneor more moieties selected from category 4) below:

-   -   5) aliphatic moieties, in particular having from 1 to 7 carbon        atoms, e.g. 1, 2, 3 or 4, particularly alkyl or alkenyl        moieties, e.g. alkyl;    -   6) carbocyclic rings, which may be saturated or unsaturated        (e.g. aromatic), particularly to be mentioned are bicyclic and        monocyclic rings and especially monocyclic rings having 5 or 6        ring members;    -   7) heterocyclic rings, which may be saturated or unsaturated        (e.g. aromatic), particularly to be mentioned are bicyclic and        monocyclic rings and especially monocyclic rings having 5 or 6        ring members;    -   8) linking moieties selected from O, N, Si and C(O), wherein two        or more linking moieties may be combined to form a larger        linking group for example C(O)O, C(O)NH or OC(O)NH.

In these compounds, a plurality of moieties selected from 1), 2) and 3)may be linked together either directly or through a linking moiety 4).Of course, one compound may contain one or more linking moieties. Tri-or more valent linking moieties such as N and Si may serve to linktogether just two moieties selected from 1), 2) and 3), in which casethe remaining valencies are suitably occupied by hydrogen; alternativelyN or Si may link together three said moieties, or Si may link togetherfour said moieties. Where Rz* contains a plurality of moieties selectedfrom 1), 2) and 3), the moieties may be the same of different and mayindependently be selected from categories 1), 2) and 3).

Moieties 1), 2) and 3) may be substituted by one or more substituentsselected from, in particular, hydroxy, amino, amidino, guanidino,hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, C(O)H orother lower acyl, lower acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl,cyano, azo, or nitro, which hydroxy, amino, amidino, guanidino,hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, carboxy,sulfo, sulfamoyl, carbamoyl and cyano groups are in turn optionallysubstituted on at least one heteroatom by one or, where possible, moreC₁-C₇ aliphatic groups. Often, but not always, Rz* has 0, 1, 2, 3, or 4such substituents; sometimes there are a larger number of substituentsas can happen, for example, when Rz* contains one or more perfluorinatedalkyl or cyclic groups, e.g. CF₃, as well as other optionalsubstituents.

Particular moieties 1), 2) and 3) to mention are straight chain andbranched alkyl, 5- and 6-membered carbocyclic rings (notably phenyl andcyclohexyl), and 5- and 6-membered heterocyclic rings (notably5-membered rings containing a single heteroatom, e.g. furan, thiophene,pyrrole; and 6-membered rings containing one or two heteroatoms, e.g.piperidine, piperazine, morpholine, pyridine, pyrimidine and pyrazine).

The invention includes compounds of Formula (I*) or (II*) wherein R¹ isof the formula Rz*-NR^(a)—, as described above, and Rz* is selected from

(i) -G-R^(x) where G is a direct bond, C(═O) or C(═O)O and R^(x) isselected from H and C₁-C₇ aliphatic moieties,(II*) -G-R^(y) where G is a direct bond, C(═O) or C(═O)O and R^(y) isselected from C₁-C₇ aliphatic substituted by one or more halogens and/orone or two functional groups selected from hydroxy, amino, amidino,guanidino, hydroxyguanidino, formamidino, isothioureido, ureido,mercapto, C(O)H or other lower acyl, lower acyloxy, carboxy, sulfo,sulfamoyl, carbamoyl, cyano, azo, or nitro, which hydroxy, amino,amidino, guanidino, hydroxyguanidino, formamidino, isothioureido,ureido, mercapto, carboxy, sulfo, sulfamoyl, carbamoyl and cyano groupsare in turn optionally substituted on at least one heteroatom by one or,where possible, more C₁-C₇ aliphatic groups,(iii) a group of the formula

-   -   where:    -   J represents a direct bond, alkyl or alkyl terminated or        interrupted by C(═O) or C(═O)O, where J has 1, 2, 3, 4 or 5        in-chain atoms;    -   ring B represents a mono- or bi-cyclic ring, particularly a 5-        or 6-membered carbocyclic or heterocyclic ring;    -   p is 0, 1, 2; 3, 4 or 5, e.g. 0, 1 or 2;    -   the or each R^(b) is independently selected from        -L⁴-NR^(c)R^(d); -L⁴-RING* where RING* is a mono- or bi-cyclic        ring, particularly a 5- or 6-membered carbocyclic or        heterocyclic ring, optionally substituted as defined below;        halogen; hydroxy; protected hydroxy for example        trialkylsilylhydroxy; amino; amidino; guanidino;        hydroxyguanidino; formamidino; isothioureido; ureido; mercapto;        C(O)H or other lower acyl; lower acyloxy; carboxy; sulfo;        sulfamoyl; carbamoyl; cyano; azo; or nitro; and C₁-C₇ aliphatic        optionally substituted by one or more halogens and/or one or two        functional groups selected from hydroxy, protected hydroxy for        example trialkylsilylhydroxy, amino, amidino, guanidino,        hydroxyguanidino, formamidino, isothioureido, ureido, mercapto,        C(O)H or other lower acyl, lower acyloxy, carboxy, sulfo,        sulfamoyl, carbamoyl, cyano, azo, or nitro; all of which        hydroxy, amino, amidino, guanidino, hydroxyguanidino,        formamidino, isothioureido, ureido, mercapto, carboxy, sulfo,        sulfamoyl, carbamoyl and cyano groups are in turn optionally        substituted on at least one heteroatom by one or, where        possible, more C₁-C₇ aliphatic groups,    -   wherein L⁴ is a direct bond; a linkage selected from —O—; —S—;        —C(O)—; —OC(O)—; —NR^(a)C(O)—; —C(O)—NR^(a)—; —OC(O)—NR^(a)—;        cyclopropyl and —NR^(a)—; or is a C₁-C₇ aliphatic group        optionally interrupted and/or terminated at a single end or at        both ends by a said linkage (R^(a) being as previously defined        and typically H);        and wherein R^(c) and R^(d) are each independently selected from        hydrogen, and C₁-C₇ aliphatic optionally substituted by one or        more halogens, by an optionally substituted 5- or 6-membered        heterocyclic or carbocyclic ring, and/or one or two functional        groups selected from hydroxy, protected hydroxy for example        trialkylsilylhydroxy, amino, amidino, guanidino,        hydroxyguanidino, formamidino, isothioureido, ureido, mercapto,        C(O)H or other lower acyl, lower acyloxy, carboxy, sulfo,        sulfamoyl, carbamoyl, cyano, azo, or nitro, which hydroxy,        amino, amidino, guanidino, hydroxyguanidino, formamidino,        isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl,        carbamoyl and cyano groups are in turn optionally substituted on        at least one heteroatom by one or more C₁-C₇ aliphatic groups,        or R^(c) and R^(d) together with their adjoining nitrogen form a        5- or 6-membered ring optionally substituted as described below,        said optionally substituted rings independently of each other        being substituted by 0, 1, 2, 3, 4 or 5 substituents selected        from halogen; hydroxy; protected hydroxy for example        trialkylsilylhydroxy; amino; amidino; guanidino;        hydroxyguanidino; formamidino; isothioureido; ureido; mercapto;        C(O)H or other lower acyl; lower acyloxy; carboxy; sulfo;        sulfamoyl; carbamoyl; cyano; azo; nitro; C₁-C₇ aliphatic        optionally substituted by one or more halogens and/or one or two        functional groups selected from hydroxy, protected hydroxy for        example trialkylsilylhydroxy, amino, amidino, guanidino,        hydroxyguanidino, formamidino, isothioureido, ureido, mercapto,        C(O)H or other lower acyl; lower acyloxy carboxy, sulfo,        sulfamoyl, carbamoyl, cyano, azo, or nitro; all of the aforesaid        hydroxy, amino, amidino, guanidino, hydroxyguanidino,        formamidino, isothioureido, ureido, mercapto, carboxy, sulfo,        sulfamoyl and carbamoyl groups in turn optionally being        substituted on at least one heteroatom by one or, where        possible, more C₁-C₇ aliphatic groups (for example, therefore, a        ring may be substituted by an alkoxy group, e.g. methoxy or        ethoxy).

Still considering compounds wherein R¹ is of the formula Rz*-NR^(a) andRz* is selected from categories (i), (ii) and (iii) above, aliphaticoften has 1, 2, 3 or 4 carbon atoms and is often linear, but sometimesbranched. In a class of compounds, aliphatic is alkyl, e.g. linear orbranched alkyl having 1, 2, 3 or 4 carbon atoms; linear alkyl is morecommon, irrespective of the number of carbon atoms.

In a sub-class of the above category (i) compounds, -G- is a direct bondand R^(x) is H or a said aliphatic group and more particularly R^(x) isH or alkyl, e.g. linear or branched alkyl having 1, 2, 3 or 4 carbonatoms; linear alkyl being more common, irrespective of the number ofcarbon atoms. This sub-class therefore comprises compounds in which R¹is amino or mono- or di-alkylamino. Included are members of thissub-class in which R^(x) is not H but a said aliphatic group.

In another sub-class of category (i) compounds, -G- is C(═O) or C(═O)Oand R^(x) is H or a said aliphatic group and more particularly R^(x) isH or alkyl, e.g. linear or branched alkyl having 1, 2, 3 or 4 carbonatoms, linear alkyl being more common, irrespective of the number ofcarbon atoms. Included are members of this sub-class in which R^(x) isnot H but a said aliphatic group. Methyl may be mentioned as anexemplary R^(x) group. It will be understood that in some compounds ofthis sub-class -G- is C(═O) whereas in other compounds G is C(═O)O. AsR¹ groups formed by this sub-class may be mentioned alkanoylamino,particularly acetylamino (—NHC(O)Me), and alkoxycarbonylamino,particularly methoxycarbonylamino (—NHC(O)OMe).

It will be appreciated from the preceding two paragraphs that theinvention includes category (i) compounds in which R^(x) is not H but asaid aliphatic group as in the case of alkyl, e.g. linear or branchedalkyl having 1, 2, 3 or 4 carbon atoms.

A particular genus of compounds are those in which R^(a) is aspreviously defined, e.g. is selected from hydrogen and aliphatic groups,particularly alkyl groups (e.g. in either case having 1 to 7 carbonatoms, for example 1, 2, 3, or 4, and R¹ is selected from the groupconsisting of:

-   -   1) moieties falling within category (i) above, wherein -G- is a        direct bond and R^(x) is H or a said aliphatic group, and        aliphatic often has 1, 2, 3 or 4 carbon atoms and is typically        linear, but sometimes branched. In a sub-genus of these        compounds, aliphatic is alkyl, e.g. linear or branched alkyl        having 1, 2, 3 or 4 carbon atoms; linear alkyl is more common,        irrespective of the number of carbon atoms;    -   2) moieties of the formula Rz*-NR^(a)—, where Rz* is acyl;        acyloxy; where acyl is particularly lower alkanoyl e.g. of which        the alkyl part has 1, 2, 3 or 4 carbon atoms;    -   3) moieties falling within category (i) above, wherein -G- is        C(═O) or C(═O)O and R^(x) is H or a said aliphatic group and        more particularly R^(x) is H or alkyl, e.g. linear or branched        alkyl having 1, 2, 3 or 4 carbon atoms, linear alkyl being more        common, irrespective of the number of carbon atoms. Included are        members of this sub-class in which R^(x) is not H but a said        aliphatic group; methyl may be mentioned as an exemplary R^(x)        group;    -   4) C₁, C₂, C₃ or C₄ alkyl, C₁, C₂, C₃ or C₄ haloalkyl (e.g.        trifluoromethyl), halo (e.g. F or Cl), hydroxy, alkoxy (e.g.        methoxy), cyano, azo (N═N═N) or nitro.

In many compounds of this genus, R^(a) is H. Commonly, Rz* is as definedin sub-clause 1) or 3) of the preceding paragraph, e.g. is H; C₁, C₂, C₃or C₄ alkyl; C₁, C₂, C₃ or C₄ alkanoyl; or alkoxycarbonyl of which thealkoxy part has 1, 2, 3 or 4 carbon atoms.

Particular compounds falling in category (ii) are those in which -G- isa direct bond. Also to be mentioned are category (ii) compounds in which-G- is C(═O) or C(═O)O.

Turning now to those compounds in which Rz* is a category (iii) group,i.e. is of the formula

ring B is typically a 6-membered carbocyclic or heterocyclic ring,particularly phenyl, cyclohexyl or cyclohexenyl. Of these, phenyl ispreferred. In other instances, ring B is a 5-membered carbocyclic orheterocyclic ring. Other exemplary residues forming ring B are pyridyland pyrimidyl.

J is often a direct bond, thus forming Fragment H of the formula:

Integer p may be 0.

Integer p is often 1. Where p is greater than one, all the R^(b) groupsor all the R^(b) groups except one are often halogen (notably F or Cl),methyl or trifluoromethyl. Also to be mentioned in this regard arehydroxy and amino. Often, a single R^(b) group is selected from-L⁴-NR^(c)R^(d) and -L⁴-RING* and there are 0, 1 or 2 additionalsubstituents which are not -L⁴-NR^(c)R^(d) or -L⁴-RING* but are, forexample, halogen (notably F or Cl), lower alkyl (e.g. methyl), loweralkoxy (e.g. methoxy), hydroxy, amino or trifluoromethyl.

Accordingly, the invention includes compounds in which Rz* is, e.g. a6-membered carbocyclic ring (notably phenyl) substituted by 1, 2, 3, 4or 5 halogens, e.g. selected from F, Cl and Br; typically, such phenylrings are mono- or di-substituted, e.g. are 2- and/or 4-substituted by For 3-substituted by Cl. In some cases of plural substitution by halogen,all the halogens are the same. Thus, in a class of compounds Rz* is amonocyclic ring, particularly a 6-membered carbocyclic ring (notablyphenyl), substituted solely by one or more halogens, particularlyselected from F and Cl; sometimes the or each halogen is F but in someother cases the or each halogen is Cl.

In another class of compounds, Rz* is a monocyclic ring, particularly a6-membered carbocyclic ring (notably phenyl), substituted by 1, 2, 3, 4or 5 substituents, e.g. 1 or 2 substituents, selected from alkyl,alkoxy, alkanoyl, alkanoyloxy, haloalkyl, amino, mono- or di-alkylamino, cyano, halogen, hydroxy or protected hydroxy, wherein alkylor the alkyl part of alkoxy and alkanoyl(oxy) has 1, 2, 3 or 4 carbonatoms; exemplary substituents in this case are methyl, ethyl, methoxy,ethoxy, acetyl, trifluoromethyl, cyano, F, Cl and OH. Certain such ringshave 0, 1 or 2 substituents, e.g. 0 or 1.

In one class of compounds, L⁴ is a direct bond, linear alkyl, linearalkyl terminated adjacent ring A by a said linkage, or is a saidlinkage. In a sub-class, any said linkage is —O—, —C(O)— or a directbond, of which —O— and a direct bond may be particularly mentioned, forexample —O—

The invention includes a class of compounds in which ring A is a6-membered ring, particularly phenyl, cyclohexyl or cyclohexenyl and hasone or two substituents R^(b) independently selected from-L⁴-NR^(c)R^(d) and -L⁴-RING*, as defined previously. In a sub-class,there is a single substituent at, in particular, the 3-position or4-position selected from -L⁴-NR^(c)R^(d) and -L⁴-RING* such that theleft hand ring has a structure corresponding to Fragments (D1), (D2),(E1) or (E2):

As previously described, R^(a) is commonly H. Also as previouslydescribed, the phenyl ring may be replaced by cyclohexyl orcyclohexenyl, particularly cyclohexyl. It may alternatively be replacedby a 5- or 6-membered heterocycle, particularly pyridine.

In some embodiments, the phenyl ring of the above fragments (or otherring replacing phenyl) has 1, 2, 3 or 4 further substituents, forexample selected from halogen (notably F or Cl), methyl, methoxy ortrifluoromethyl, e.g. 1 or 2 such substituents. Also to be mentioned inthis regard are hydroxy and amino.

L⁴ is as previously described, that is a direct bond; a linkage selectedfrom —O—; —S—; —C(O)—; —OC(O)—; —NR^(a)C(O)—; —C(O)—NR^(a)—;—OC(O)—NR^(a); cyclopropyl and —NR^(a)—; or C₁-C₇ aliphatic optionallyinterrupted and/or terminated at a single end or at both ends by a saidlinkage (R^(a) being as previously defined and typically H). Anyaliphatic moiety is often alkyl, e.g. alkyl or other aliphatic having 1,2, 3 or 4 carbon atoms, as in the case of a sub-class of linkers L² inwhich aliphatic moieties are methyl, ethyl or n-propyl.

In particular fragments (D) and (E), L⁴ is a direct bond, linear alkyl,linear alkyl terminated adjacent the phenyl ring in the aboverepresentations of the fragments by a said linkage, or is a saidlinkage; suitably but not necessarily any said linkage is —O— or —C(O)—,of which —O— may be particularly mentioned. Thus, the above fragments(D) and (E) may comprise sub-fragments -Ph-NR^(c)R^(d), -Ph-RING*,-Ph-O-alkyl-NR^(c)R^(d), -Ph-O-alkyl-RING*, -Ph-alkyl-NR^(c)R^(d),-Ph-alkyl-RING*, and also to be mentioned are sub-fragments-Ph-O—NR^(c)R^(d), -Ph-O-RING*, -Ph-C(O)—NR^(c)R^(d) and -Ph-C(O)—RING*,where, in all these sub-fragments which contain alkyl, alkyl may be e.g.methyl, ethyl or n-propyl, or n-butyl.

In some embodiments L⁴ is H, thus providing fragment (E3) and (E4):

Considering now in more detail fragments (D1) and (D2), these contain amoiety RING* which is a cyclic moiety and in many cases a 5- or6-membered carbocyclic or heterocyclic ring optionally substituted asdefined previously. Exemplary rings are saturated, e.g. cyclopentane orcyclohexane. In particular compounds, RING* is a 5- or 6-memberedheterocycle, often containing one or two heteroatoms, typically selectedfrom O and N; in a sub-class, the heterocycles contain one or twonitrogens and, where there is a single nitrogen, optionally an oxygen.Particular heterocycles include a nitrogen which is not a member of adouble bond and these are more particularly saturated heterocycles. Asheterocycles may be mentioned pyrrolidine, piperidine, piperazine andmorpholine; in some compounds, RING* is piperidine having its nitrogenat the 4-position relative to L². As already described, RING* may besubstituted and, in one class of compounds, is substituted by 0, 1, 2,3, 4 or 5 substituents, e.g. selected from C₁-C₇ aliphatic groups,optionally substituted as described above, and less frequently C₁-C₇aliphatic-oxy. Any aliphatic group is often alkyl (straight chain orbranched), e.g. alkyl or other aliphatic having 1, 2, 3 or 4 carbonatoms, as in the case of a sub-class of fragments (D1) and (D2) havingsubstituents which are methyl, ethyl or n-propyl. Exemplary substituentson RING* include straight chain or branched C₁, C₂, C₃ or C₄ alkyl suchas, e.g., methyl, ethyl n-propyl, isopropyl or t-butyl, of which methylmay be particularly mentioned, halogen (notably F or Cl) and C₁, C₂, C₃or C₄ alkoxy; also to be mentioned are hydroxy and amino. Alkyl moietiesmay be unsubstituted or substituted, e.g. by halogen (notably F or Cl)or in some cases by hydroxy or amino.

In some classes of RING* moieties, there are 0, 1, 2, 3, 4 or 5 suchsubstituents selected from alkyl, alkoxy, alkanoyl, alkanoyloxy,haloalkyl, amino, mono- or di-alkylamino, cyano, halogen, hydroxy orprotected hydroxy, wherein alkyl or the alkyl part of alkoxy andalkanoyl(oxy) has 1, 2, 3 or 4 carbon atoms; exemplary substituents inthis case are methyl, ethyl, methoxy, ethoxy, acetyl, trifluoromethyl,cyano, F, Cl and OH. Certain RING* moieties have 0, 1 or 2 substituents,e.g. 0 or 1.

Considering now in more detail fragments (E1) and (E2), these contain amoiety NR^(c)R^(d). R^(c) and R^(d) are as previously described. In oneclass of these fragments, R^(c) and R^(d) are the same or different (butmore usually the same) and selected from C₁-C₇, e.g. C₁-C₄ aliphaticgroups, optionally substituted as described above. As aliphatic R^(c)and R^(d) moieties may be mentioned alkyl, e.g having 1, 2, 3 or 4carbon atoms, as in the case of a sub-class of fragments (E1) and (E2)having substituents which are methyl, ethyl or n-propyl. Alkyl or otheraliphatic moieties may be substituted e.g. by amino or mono- or di(C₁-C₄) alkylamino, or e.g. by a 5- or 6-membered heterocyclic orcarbocyclic ring optionally substituted as previously described, or beunsubstituted. Thus, particular L⁴NR^(c)R^(d) moieties are —OCH₂NMe₂,—OCH₂NEt₂, —OCH₂CH₂NMe₂, —OCH₂CH₂NEt₂, —OCH₂CH₂CH₂NMe₂, —OCH₂CH₂CH₂NEt₂, —CH₂NMe₂, —CH₂NEt₂, —CH₂CH₂NMe₂, —CH₂CH₂NEt₂, —CH₂CH₂CH₂NMe₂,and —CH₂CH₂CH₂NEt₂.

In some compounds, R^(c) and R^(d) may each independently contain acarbonyl moiety. Where one of R^(c) or R^(d) contain a carbonyl moiety,the carbonyl moiety may form, for example, an amide bond with thenitrogen. Derivatives including an amide bond include moietiesterminating in a carbocyclic acid residue or an ester, for example analkyl ester, for example a methyl or ethyl ester. Typically compoundscontaining a carbonyl moiety are of the form of an ester.

Typically, when one of R^(c) or R^(d) contain a carbonyl moiety, theother of R^(c) or R^(d) is hydrogen.

In one class of fragments, L⁴ is a direct bond and R^(c) and R^(d) areeach independently selected from hydrogen, —C(O)-alkyl, —C(O)-alkylwhere alkyl may be substituted or unsubstituted. Typically, alkyl is C₁,C₂, C₃ or C₄ alkyl such as, for example, methyl, ethyl, n-propyl,isopropyl or t-butyl, of which methyl may be particularly mentioned.

In another class of fragments (E1) and (E2), R^(c) and R^(d) togetherwith the adjoining nitrogen form a heterocyclic moiety (normally a 5- or6-membered heterocyclic ring), optionally substituted as previouslydescribed. In addition to the nitrogen of moiety NR^(c)R^(d), theheterocyclic ring may contain at least one further heteroatom, and oftenexactly one further heteroatom, in either case typically selected from Oand N; in a sub-class, the heterocycles contain altogether one or twonitrogens and, where there is a single nitrogen, optionally an oxygen.Particular heterocycles include a nitrogen which is not a member of adouble bond and these are more particularly saturated heterocycles. Asheterocycles may be mentioned pyrrolidine, piperidine, piperazine andmorpholine; of these particular heterocycles are piperazine andmorpholine. As already described, the heterocycle may be substitutedand, in one class of compounds, is substituted by 0, 1, 2, 3, 4 or 5substituents, e.g. selected from C₁-C₇ aliphatic groups, optionallysubstituted as described above, and less frequently C₁-C₇ aliphatic-oxy.Any aliphatic group is often alkyl (straight chain or branched), e.g.alkyl or other aliphatic having 1, 2, 3 or 4 carbon atoms, as in thecase of a sub-class of cyclic (E1) and (E2) fragments havingsubstituents which are methyl, ethyl or n-propyl. Exemplary substituentson cyclic (E1) and (E2) fragments include straight chain or branched C₁,C₂, C₃ or C₄ alkyl such as, e.g., methyl, ethyl n-propyl, isopropyl ort-butyl, of which methyl may be particularly mentioned, halogen (notablyF or Cl) and C₁, C₂, C₃ or C₄ alkoxy; also to be mentioned are hydroxyand amino. Alkyl moieties may be unsubstituted or substituted, e.g. byhalogen (notably F or Cl) or in some cases by hydroxy or amino.

In some classes of cyclic (E1) and (E2) fragments (that is to sayfragments in which R^(c) and R^(d) together with the adjoining nitrogenform a ring), there are 0, 1, 2, 3, 4 or 5 such substituents selectedfrom alkyl, alkoxy, alkanoyl, alkanoyloxy, haloalkyl, amino, mono- ordi-alkylamino, cyano, halogen, hydroxy or protected hydroxy, whereinalkyl or the alkyl part of alkoxy and alkanoyl(oxy) has 1, 2, 3 or 4carbon atoms; exemplary substituents in this case are methyl, ethyl,methoxy, ethoxy, acetyl, trifluoromethyl, cyano, F, Cl and OH. Certaincyclic fragments have 0, 1 or 2 substituents, e.g. 0 or 1.

Particular L⁴NR^(c)R^(d) moieties are -Pip, -Morph, —OCH₂Pip,—OCH₂-Morph, —OCH₂CH₂Pip, —OCH₂CH₂-Morph, —OCH₂CH₂CH₂Pip,—OCH₂CH₂CH₂-Morph, —CH₂Pip, —CH₂-Morph, —CH₂CH₂Pip, —CH₂CH₂-Morph,—CH₂CH₂CH₂Pip, and —CH₂CH₂CH₂-Morph. Also to be mentioned are —C(O)Pipand —C(O)Morph. The abbreviation “Pip” stands for piperazine and “Morph”for morpholine, and these rings may be substituted as previouslydescribed. In particular piperazine is optionally N-substituted.Piperazine and morpholine may be substituted by a C₁-C₇ aliphatic groupas mentioned in the previous paragraph, for example a straight chain orbranched C₁, C₂, C₃ or C₄ moiety selected from alkyl and haloalkyl suchas, e.g., methyl, trifluoromethyl, ethyl n-propyl, isopropyl or t-butyl,of which methyl and trifluoromethyl are exemplary. As described before,R^(a) is in particular hydrogen.

Amongst the classes of compounds which are particularly to be mentionedare those in which the left hand ring has a structure corresponding toFragment (D1*) or (E1). Particularly exemplary are such compounds havinga Fragment (E1*) in which R^(c) and R^(d) together with the adjoiningnitrogen form a 5- or 6-membered heterocyclic ring as described above.These rings may be substituted as previously described. In particularthey are optionally N-substituted by a C₁-C₇ aliphatic group asmentioned earlier, for example a straight chain or branched C₁, C₂, C₃or C₄ moiety selected from alkyl and haloalkyl such as, e.g., methyl,trifluoromethyl, ethyl n-propyl, isopropyl or t-butyl, of which methyland trifluoromethyl are exemplary. As described before, R^(a) is inparticular hydrogen.

It will be appreciated from the aforegoing that the invention includescompounds having a left hand ring having the structure of the followingFragment (F*):

where R^(w) is selected from the group consisting of:(i) H; C₁, C₂, C₃ or C₄ alkyl; C₁, C₂, C₃ or C₄ alkanoyl; oralkoxycarbonyl of which the alkoxy part has 1, 2, 3 or 4 carbon atoms,(ii) 4-phenyl or 4-phenyl substituted by -L⁴NR^(c)R^(d), where-L⁴NR^(c)R^(d) is as defined previously and in particular is:

-   -   (a) -Pip, -Morph, —OCH₂Pip, —OCH₂-Morph, —OCH₂CH₂Pip,        —OCH₂CH₂-Morph, —OCH₂CH₂CH₂Pip, —OCH₂CH₂CH₂-Morph, —CH₂Pip,        —CH₂-Morph, —CH₂CH₂Pip, —CH₂CH₂-Morph, —CH₂CH₂CH₂Pip, or        —CH₂CH₂CH₂-Morph, or is —C(O)Pip or —C(O)Morph, where “Pip” and        “Morph” are as described in the last but one paragraph; or    -   (b) —OCH₂NMe₂, —OCH₂NEt₂, —OCH₂CH₂NMe₂, —OCH₂CH₂NEt₂,        —OCH₂CH₂CH₂NMe₂, —OCH₂CH₂CH₂NEt₂, —CH₂NMe₂, —CH₂NEt₂,        —CH₂CH₂NMe₂, —CH₂CH₂NEt₂, —CH₂CH₂CH₂NMe₂, or —CH₂CH₂CH₂NEt₂.

In certain compounds, R^(w) is H, formyl, acetyl or methoxycarbonyl.

In embodiments, the pyrimidine rings of Fragments (D1), (D2), (E1), (E2)and (F) are replaced by a pyridine or triazine ring.

Substituent R³

Substituent R³ is as previously described in relation to Formula (I*) or(II*).

In embodiments, R³ is selected from H, R^(b) groups, and categories (i),(ii) and (iii) described above in relation to Rz*, independently of theidentity of Rz*. In one class of embodiments, R³ is H or a C₁-C₇aliphatic group, for example straight chain or branched C₁-C₄ alkyl suchas, e.g., methyl, ethyl or n-propyl, of which methyl is exemplary. Inother compounds, R³ is a C₁-C₇ aliphatic group (for example straightchain or branched C₁-C₄ alkyl such as, e.g., methyl, ethyl or n-propyl)substituted by a mono- or bi-cyclic ring, particularly a 5- or6-membered saturated or unsaturated carbocyclic or heterocyclic ring,for example by phenyl, pyrrolidine, piperidine, piperazine, morpholine,thiophene, furan, pyrrole, pyridine, pyrazine or pyran. R³ may thereforebe straight chain alkyl (or other straight chain aliphatic group, forexample in either case having up to 4 carbon atoms) substituted at itsfree end by such a mono- or bi-cyclic ring.

In one class of compounds R³ is a category (iii) moiety, that is, it isin particular a moiety having the structure of Fragment H:

as previously described. The identity of R³ is independent of that ofRz*, as already stated.

However, as particular compounds, may be mentioned those in which justone of Rz* and R³ is a category (iii) moiety. In a subclass, one of Rz*and R³ is a category (iii) moiety and the other is H; to be mentioned inthis regard are compounds in which R³ is a category (iii) moiety and R¹is NH₂, or alternatively mono- or di-alkyl amino.

Where R³ is a category (iii) moiety, it may have a structurecorresponding to the category (iii) structures found in Fragments (D1),(D2), (E1), (E2) or (F), as previously described.

In many compounds R³ is H; where it is not H it is often C₁, C₂, C₃ orC₄ alkyl (e.g. ethyl or methyl). It may also be, for example, such analkyl group substituted, e.g. at a free end thereof, by a 5- or6-membered heterocyclic ring; typically the ring is saturated, forexample it may be selected from piperidine, piperizine, thiazolidine,morpholine and thiomorpholine

The Right Hand Ring

By the “right hand ring” is meant the Fragment (G*):

It has previously been mentioned that: n is 0, 1, 2, 3 or 4; m is m is0, 1, 2, 3, 4 or 5; each R⁴ is the same or different and selected fromorganic and inorganic moieties; L¹ is a linker; ring A is a mono- orbicyclic ring; and each R¹⁶ is the same or different and selected fromorganic and inorganic moieties.

Integer m is normally 1. Typically, there is an L¹ group at the3-position of the phenyl ring relative to L¹. Accordingly, preferredcompounds are of Formula (III*):

In Formulae (I*) and (II*), L¹ is typically a linker L¹¹ selected from—NR^(a)CO— and —CONR^(a)—, in which R^(a) is as previously defined andis typically H or lower (e.g. 1, 2, 3 or 4C) alkyl, particularly H. L¹is more especially —NR^(a)CO—, e.g. —NHCO—, to form compounds of Formula(IV*):

Integer n is often 0, 1, 2 or 3, e.g. 0, 1 or 2. In one class ofcompounds, n is 0; in another, n is 1.

In embodiments, each R⁴ is the same or different and selected fromhalogen; hydroxy; protected hydroxy for example trialkylsilylhydroxy;amino; amidino; guanidino; hydroxyguanidino; formamidino; isothioureido;ureido; mercapto; C(O)H or other acyl; acyloxy; carboxy; sulfo;sulfamoyl; carbamoyl; cyano; azo; nitro; C₁-C₇ aliphatic optionallysubstituted by one or more halogens and/or one or two functional groupsselected from hydroxy, protected hydroxy for exampletrialkylsilylhydroxy, amino, amidino, guanidino, hydroxyguanidino,formamidino, isothioureido, ureido, mercapto, C(O)H or other acyl,acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, or nitro; allof the aforesaid hydroxy, amino, amidino, guanidino, hydroxyguanidino,formamidino, isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyland carbamoyl groups in turn optionally being substituted on at leastone heteroatom by one or, where possible, more C₁-C₇ aliphatic groups(for example, therefore, R⁴ may be an alkoxy group, e.g. methoxy orethoxy).

R⁴ is particularly selected from hydroxy, protected hydroxy, loweralkoxy, lower alkyl, trifluoromethyl and halo, notably F or Cl. R⁴ mayalso be Br. Alkyl and the alkyl part of alkoxy may be branched or, moreusually, straight chain, and often have 1, 2, 3, or 4 carbon atoms, asfor example in the case of methyl, ethyl, methoxy and ethoxy. R⁴ isespecially selected from Cl, F, hydroxy, methyl, methoxy andtrifluoromethyl, e.g. is selected from Cl, F, methyl, methoxy andtrifluoromethyl, as in those compounds where R⁴ is Cl, F, methyl ormethoxy. In certain compounds. R⁴ is methyl or methoxy, of which methylmay be mentioned in particular. In some of the compounds mentioned inthis paragraph, chlorine is the sole halogen, in some others fluorine isthe sole halogen. The reader is reminded that, where there are plural R⁴groups, they may be the same or different.

In a particular class of compounds, n is 1, i.e. there is a single R⁴group, such as methyl, methoxy or trifluoromethyl, for example.

Included are compounds in which there is an R⁴ group at one or bothortho positions, relative to the urea moiety (—NR³C(O)NH—). Alsoincluded in the invention are compounds in which there is a single R⁴group (e.g. methyl, methoxy or trifluoromethyl), which is at the6-position relative to the urea moiety. Accordingly, there are includedcompounds of the formula (V*):

where R^(4a) and R^(4b) are each independently selected from H, halo(especially F or Cl), alkyl, haloalkyl or alkoxy, wherein alkyl and thealkyl part of alkoxy are branched or straight chain and often have 1, 2,3, or 4 carbon atoms; in embodiments, R^(4a) and R^(4b) may additionallybe selected from hydroxy and amino. Typically R^(4a) is H, alkyl,haloalkyl, or alkoxy, for example H, lower alkyl, lower haloalkyl orlower alkoxy, such as H, methyl, ethyl, trifluoromethyl, methoxy orethoxy, for example. In a particular class of compounds R^(4c) is H,methyl or methoxy or, in another class is trifluoromethyl. Typically,R^(4b) is H or alkoxy, such as methoxy or ethoxy, for example.

Included are embodiments in which at least one of R^(4a) or R^(4b) isnot H as well as embodiments in which both of R^(4a) or R^(4b) are H. Inone particular class of compounds, one of R^(4a) or R^(4b) is H and theother is not H.

Frequently, there is no R⁴ group. For example, in particular compoundsthere is no R⁴ group, and either (i) R^(4a) is methyl or methoxy or, insome case, trifluoromethyl and R^(4b) is H, or (ii) R^(4a) is H andR^(4b) is methoxy.

In embodiments, each R¹⁶ is the same or different and selected fromhalogen; hydroxy; protected hydroxy for example trialkylsilylhydroxy;amino; amidino; guanidino; hydroxyguanidino; formamidino; isothioureido;ureido; mercapto; C(O)H or other acyl; acyloxy; carboxy; sulfo;sulfamoyl; carbamoyl; cyano; azo; nitro; C₁-C₇ aliphatic optionallysubstituted by one or more halogens and/or one or two functional groupsselected from hydroxy, protected hydroxy for exampletrialkylsilylhydroxy, amino, amidino, guanidino, hydroxyguanidino,formamidino, isothioureido, ureido, mercapto, C(O)H or other acyl,acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, or nitro; allof the aforesaid hydroxy, amino, amidino, guanidino, hydroxyguanidino,formamidino, isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyland carbamoyl groups in turn optionally being substituted on at leastone heteroatom by one or, where possible, more C₁-C₇ aliphatic groups(for example, therefore, R16 may be an alkoxy group, e.g. methoxy orethoxy).

Ring A and any substituents R¹⁶ will for convenience be referred tosubsequently as Fragment I:

Fragment I may have any structure described herein for Fragment H, andmay be the same as Fragment H, if present, or different. Thus, Ring Amay be a mono- or bi-cyclic ring, particularly a 5- or 6-memberedcarbocyclic or heterocyclic ring, for example phenyl, cyclohexyl orcyclohexenyl. Of these, phenyl is preferred. In other instances, ring Ais a 5-membered carbocyclic or heterocyclic ring. Other exemplaryresidues forming ring A are pyridyl and pyrimidyl.

Integer m is often 0, 1, 2 or 3, for example 0, 1 or 2, as in the caseof compounds where m is 0 or 1. For example, where ring A is a6-membered ring, there is often a substituent at the 3- or 4-position.

Interger m is often 1. Where m is greater than 1, all the R¹⁶ groupsexcept 1 are often halogen (notably F or Cl), methyl or trifluoromethyl.Also to be mentioned in this regard are hydroxyl and amino. Often asingle R¹⁶ group is selected from -L⁵-NR^(c)R^(d) and -L⁵-RING* andthere are 0, 1 or 2 additional substituants which are not-L⁵-NR^(c)R^(d) or -L⁵-RING* but are, for example, halogen (notably F orCl), lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy), hydroxyl,amino or trifluoromethyl.

Accordingly, the invention includes compounds in which R¹⁶ is, e.g. a6-membered carbo cyclic ring (notably phenyl) substituted by 1, 2, 3, 4or 5 halogens, e.g. selected from F, Cl and Br; typically, such phenylrings are mono- or di-substituted, e.g. R² and/or 4-substituted by F or3-substituted by Cl. In some cases of plural substitution by halogen,all the halogens are the same. Thus, in a class of compounds R¹⁶ is amonocyclic ring, particularly a 6-membered carbocyclic ring (notablyphenyl), substituted solely by one or more halogens, particularlyselected from F and Cl; sometimes V or each halogen is F but in someother cases V or each halogen is Cl.

In another class of compounds, R¹⁶ is a monocyclic ring, particulary a6-membered carbocyclic ring (notably phenyl), substituted by 1, 2, 3, 4or 5 substituents, e.g. 1 or 2 substituents, selected from alkyl alkoxyalkanoyl, alkanoyl oxy, halo alkyl, amino, mono- or di-alkyl amino,cyano, halogen, hydroxy or protected hyrdoxy, where alkyl or the alkylpart of alkoxy and alkanoyl (oxy) has 1, 2, 3 or 4 carbon atoms;exemplary substituents in this case are methyl, ethyl, methoxy, ethoxy,acetyl, trifluoromethyl, cyano, F, Cl and OH. Certain such rings have 0,1 or 2 substituents, e.g. 0 or 1.

In one class of compounds, L⁵ is a direct bond, linear alkyl, linealalkyl terminated by a moiety RING*. In a sub-class, L⁵ is —O or —C(O)—or linear alkyl having 1, 2, 3, or 4, in -chain carbon atoms, or which—CH₂— may be particularly mentioned as may —C(O)—.

The invention includes a class of compounds in which ring A is asix-membered ring, particularly phenyl, cyclohexyl or cyclohexenyl andhas 1 or 2 substituents R¹⁶ indepdendetly selected from -L⁵-NR^(c)R^(d)and -L⁵-RING*, as defined previously. In a sub-class, there is a singlesubstituent at, in particular, the 3-position or 4-position selectedfrom -L⁵-NR^(c)R^(d) and -L⁵-RING* such that the right hand ring has astructure corresponding to fragments (J1), (J2), K1), (K2) or (JK):

In some embodiments, the phenyl ring of the above fragments (J1), (J2),K1), (K2) or (JK) (or other ring replacing phenyl, such as cyclohexyl,for example) has 1, 2, 3 or 4 further substituents, for example selectedfrom halogen (notably F or Cl), methyl, methoxy or trifluoromethyl, e.g.1 or 2 such substituents. Also to be mentioned in this regard arehydroxy and amino.

L⁵ is as previously described, that is a direct bond; a linkage selectedfrom —O—; —S—; —C(O)—; —OC(O)—; —NR^(a)C(O)—; —C(O)—NR^(a);—OC(O)—NR^(a)—; cyclopropyl and —NR^(a)—; or C₁-C₇ aliphatic optionallyinterrupted and/or terminated at a single end or at both ends by a saidlinkage (R^(a) being as previously defined and typically H). Anyaliphatic moiety is often alkyl, e.g. alkyl or other aliphatic having 1,2, 3 or 4 carbon atoms, as in the case of a sub-class of linkers L² inwhich aliphatic moieties are methyl, ethyl or n-propyl.

In particular fragments (J) and (K), L² is a direct bond, linear alkyl,linear alkyl terminated adjacent the phenyl ring in the aboverepresentations of the fragments by a said linkage, or is a saidlinkage; suitably but not necessarily any said linkage is —O— or —C(O)—,of which —O— may be particularly mentioned. Thus, the above fragments(J) and (K) may comprise sub-fragments -Ph-NR^(c)R^(d), -Ph-RING″,-Ph-O-alkyl-NR^(c)R^(d), -Ph-O-alkyl-RING*, -Ph-alkyl-NR^(c)R^(d),-Ph-alkyl-RING*, and also to be mentioned are sub-fragments-Ph-O—NR^(c)R^(d), -Ph-O-RING*, -Ph-C(O)—NR^(c)R^(d) and -Ph-C(O)—RING*,where, in all these sub-fragments which contain alkyl, alkyl may be e.g.methyl, ethyl or n-propyl, or n-butyl.

In fragment (JK), the linker L⁵ may be the same or different.

Considering now in more detail fragments (K1) and (K2), these contain amoiety RING* which is a cyclic moiety and in many cases a 5- or6-membered carbocyclic or heterocyclic ring optionally substituted asdefined previously. Exemplary rings are saturated, e.g. cyclopentane orcyclohexane. In particular compounds, RING* is a 5- or 6-memberedheterocycle, often containing one or two heteroatoms, typically selectedfrom O and N; in a sub-class, the heterocycles contain one or twonitrogens and, where there is a single nitrogen, optionally an oxygen.Particular heterocycles include a nitrogen which is not a member of adouble bond and these are more particularly saturated heterocycles. Asheterocycles may be mentioned pyrrolidine, piperidine, piperazine andmorpholine; in some compounds, RING* is piperidine having its nitrogenat the 4-position relative to L². As already described, RING* may besubstituted and, in one class of compounds, is substituted by 0, 1, 2,3, 4 or 5 substituents, e.g. selected from C₁-C₇ aliphatic groups,optionally substituted as described above, and less frequently C₁-C₇aliphatic-oxy. Any aliphatic group is often alkyl (straight chain orbranched), e.g. alkyl or other aliphatic having 1, 2, 3 or 4 carbonatoms, as in the case of a sub-class of fragments (H1) and (H2) havingsubstituents which are methyl, ethyl or n-propyl. Exemplary substituentson RING* include straight chain or branched C1, C2, C3 or C4 alkyl suchas, e.g., methyl, ethyl n-propyl, isopropyl or t-butyl, of which methylmay be particularly mentioned, halogen (notably F or Cl) and C₁, C₂, C₃or C₄ alkoxy; also to be mentioned are hydroxy and amino. Alkyl moietiesmay be unsubstituted or substituted, e.g. by halogen (notably F or Cl)or in some cases by hydroxy or amino.

In some classes of RING* moieties, there are 0, 1, 2, 3, 4 or 5 suchsubstituents selected from alkyl, alkoxy, alkanoyl, alkanoyloxy,haloalkyl, amino, mono- or di-alkylamino, cyano, halogen, hydroxy orprotected hydroxy, wherein alkyl or the alkyl part of alkoxy andalkanoyl(oxy) has 1, 2, 3 or 4 carbon atoms; exemplary substituents inthis case are methyl, ethyl, methoxy, ethoxy, acetyl, trifluoromethyl,cyano, F, Cl and OH. Certain RING* moieties have 0, 1 or 2 substituents,e.g. 0 or 1.

Considering now in more detail fragments (J1) and (J2), these contain amoiety NR^(c)R^(d). R^(c) and R^(d) are as previously described. In oneclass of these fragments, R^(c) and R^(d) are the same or different (butmore usually the same) and selected from C₁-C₇, e.g. C₁-C₄ aliphaticgroups, optionally substituted as described above. As aliphatic R^(c)and R^(d) moieties may be mentioned alkyl, e.g having 1, 2, 3 or 4carbon atoms, as in the case of a sub-class of fragments (J1) and (J2)having substituents which are methyl, ethyl or n-propyl. Alkyl or otheraliphatic moieties may be substituted e.g. by amino or mono- or di(C₁-C₄) alkylamino, or e.g. by a 5- or 6-membered heterocyclic orcarbocyclic ring optionally substituted as previously described, or beunsubstituted. Thus, particular L²NR^(c)R^(d) moieties are —

OCH₂NMe₂, —OCH₂NEt₂, —OCH₂CH₂NMe₂, —OCH₂CH₂NEt₂, —OCH₂CH₂CH₂NMe₂,—OCH₂CH₂C H₂NEt₂, —CH₂NMe₂, —CH₂NEt₂, —CH₂CH₂NMe₂, —CH₂CH₂NEt₂,—CH₂CH₂CH₂NMe₂, and —CH₂CH₂CH₂NEt₂.

In another class of fragments (J1) and (J2), R^(c) and R^(d) togetherwith the adjoining nitrogen form a heterocyclic moiety (normally a 5- or6-membered heterocyclic ring), optionally substituted as previouslydescribed. In addition to the nitrogen of moiety NR^(c)R^(d), theheterocyclic ring may contain at least one further heteroatom, and oftenexactly one further heteroatom, in either case typically selected from Oand N; in a sub-class, the heterocycles contain altogether one or twonitrogens and, where there is a single nitrogen, optionally an oxygen.Particular heterocycles include a nitrogen which is not a member of adouble bond and these are more particularly saturated heterocycles. Asheterocycles may be mentioned pyrrolidine, piperidine, piperazine andmorpholine; of these particular heterocycles are piperazine andmorpholine. As already described, the heterocycle may be substitutedand, in one class of compounds, is substituted by 0, 1, 2, 3, 4 or 5substituents, e.g. selected from C₁-C₇ aliphatic groups, optionallysubstituted as described above, and less frequently C₁-C₇ aliphatic-oxy.Any aliphatic group is often alkyl (straight chain or branched), e.g.alkyl or other aliphatic having 1, 2, 3 or 4 carbon atoms, as in thecase of a sub-class of cyclic (K₁) and (K₂) fragments havingsubstituents which are methyl, ethyl or n-propyl. Exemplary substituentson cyclic (K₁) and (K₂) fragments include straight chain or branched C1,C2, C3 or C4 alkyl such as, e.g., methyl, ethyl n-propyl, isopropyl ort-butyl, of which methyl may be particularly mentioned, halogen (notablyF or Cl) and C₁, C₂, C₃ or C₄ alkoxy; also to be mentioned are hydroxyand amino. Alkyl moieties may be unsubstituted or substituted, e.g. byhalogen (notably F or Cl) or in some cases by hydroxy or amino. In someclasses of cyclic (J1) and (J2) fragments (that is to say fragments inwhich R^(c) and R^(d) together with the adjoining nitrogen form a ring),there are 0, 1, 2, 3, 4 or 5 such substituents selected from alkyl,alkoxy, alkanoyl, alkanoyloxy, haloalkyl, amino, mono- or di-alkylamino,cyano, halogen, hydroxy or protected hydroxy, wherein alkyl or the alkylpart of alkoxy and alkanoyl(oxy) has 1, 2, 3 or 4 carbon atoms;exemplary substituents in this case are methyl, ethyl, methoxy, ethoxy,acetyl, trifluoromethyl, cyano, F, Cl and OH. Certain cyclic fragmentshave 0, 1 or 2 substituents, e.g. 0 or 1.

Particular L²NR^(c)R^(d) moieties are -Pip, -Morph, —OCH₂Pip,—OCH₂-Morph, —OCH₂CH₂Pip, —OCH₂CH₂-Morph, —OCH₂CH₂CH₂Pip,—OCH₂CH₂CH₂-Morph, —CH₂Pip, —CH₂-Morph, —CH₂CH₂Pip, —CH₂CH₂-Morph,—CH₂CH₂CH₂Pip, and —CH₂CH₂CH₂-Morph. Also to be mentioned are —C(O)Pipand —C(O)Morph. The abbreviation “Pip” stands for piperazine and “Morph”for morpholine, and these rings may be substituted as previouslydescribed. In particular piperazine is optionally N-substituted.Piperazine and morpholine may be substituted by a C₁-C₇ aliphatic groupas mentioned in the previous paragraph, for example a straight chain orbranched C₁, C₂, C₃ or C₄ moiety selected from alkyl and haloalkyl suchas, e.g., methyl, trifluoromethyl, ethyl n-propyl, isopropyl or t-butyl,of which methyl and trifluoromethyl are exemplary. As described before,R^(a) is in particular hydrogen.

Amongst the classes of compounds which are particularly to be mentionedare those in which the left hand ring has a structure corresponding toFragment (J1) or (K1). Particularly exemplary are such compounds havinga fragment (K1) in which R^(c) and R^(d) together with the adjoiningnitrogen form a 5- or 6-membered heterocyclic ring as described above.These rings may be substituted as previously described. In particularthey are optionally N-substituted by a C₁-C₇ aliphatic group asmentioned earlier, for example a straight chain or branched C₁, C₂, C₃or C₄ moiety selected from alkyl and haloalkyl such as, e.g., methyl,trifluoromethyl, ethyl n-propyl, isopropyl or t-butyl, of which methyland trifluoromethyl are exemplary. As described before, R^(a) is inparticular hydrogen.

To be mentioned are right hand rings corresponding to Fragment (L):

-   -   where:    -   R^(4a) and R^(4b) are as previously defined;    -   Q and U are the same or different and selected from H, F and Cl,        e.g. are both H;    -   T and V are the same or different and selected from H, methyl,        trifluoromethyl and methoxy, e.g. from H and trifluoromethyl, as        in the case where one of T and V is H and the other is        trifluoromethyl;    -   Y² is selected from H, C₁, C₂, C₃ or C₄ alkyl (e.g. methyl or        ethyl), which may be unsubstituted or substituted, for example        at a free end thereof, by a 5 or 6 membered heterocyclic ring        optionally substituted by 1C, 2C, 3C or 4C alkyl; typically the        optionally substituted ring is saturated and may be selected        from, for example, piperidine, 4-(C₁-C₄)alkylpiperidine,        piperazine, 4-(C₁-C₄)alkylpiperazine, thiazolidine, morpholine        or thiomorpholine.

A particular right hand ring is Fragment (M):

where R^(4a) and R^(4b) are as previously defined.

To be mentioned are right hand rings corresponding to Fragment (N):

-   -   where:    -   R^(4a) and R^(4b) are as previously defined;    -   K is selected from H, methyl, trifluoromethyl and methoxy, and        in particular is H or trifluoromethyl; and    -   D is selected from 1C, 2C, 3C and 4C alkyl, and 1C, 2C, 3C or 4C        alkyl substituted by piperidine, 4-(C₁-C₄)alkylpiperidine,        piperazine, 4-(C₁-C₄)alkylpiperazine, thiazolidine, morpholine        or thiomorpholine. A particular D group is 4-methylpiperazine;        for example in many compounds D is 4-methylpiperazine and K is H        or trifluoromethyl.

In fragments L and N, alkyl is particularly linear alkyl and in manycases is methyl.

Any formula disclosed herein may have its illustrated right hand ringreplaced by a right hand ring of formula L, M or N.

The Compounds of Formula (I*)

It has been described above how the compounds of formula (I*) have thefollowing variable domains:

-   -   left hand ring    -   R³    -   right hand ring.

Various particular moieties have been described for each of thesevariable domains and it will be appreciated that any combination of suchmoieties is permissible.

To be mentioned are compounds having the following combinations, amongstmany others:

Left hand ring R³ Right hand ring Fragment (A*) H, C₁-C₄ alkyl or C₁-C₄alkyl n = 1, 2, 3, or 4. substituted by an optionally R⁴ = selected fromCl, F, substituted 5- or 6- hydroxy, methyl, methoxy, membered ringtrifluoromethyl, and alkyl substituted by an optionally substituted 5-or 6- membered ring Fragment (B*) H, C₁-C₄ alkyl or C₁-C₄ alkyl n = 1,2, 3, or 4. substituted by an optionally R⁴ = selected from Cl, F,substituted 5- or 6- hydroxy, methyl, methoxy, membered ringtrifluoromethyl, and alkyl substituted by an optionally substituted 5-or 6- membered ring Fragment (C*) H, C₁-C₄ alkyl or C₁-C₄ alkyl n = 1,2, 3, or 4. substituted by an optionally R⁴ = selected from Cl, F,substituted 5- or 6- hydroxy, methyl, methoxy, membered ringtrifluoromethyl, and alkyl substituted by an optionally substituted 5-or 6- membered ring Fragment (C*), R^(a) = H, H, C₁-C₄ alkyl or C₁-C₄alkyl n = 1, 2, 3, or 4. Rz* = category (i) or (ii) substituted by anoptionally R⁴ = selected from Cl, F, substituted 5- or 6- hydroxy,methyl, methoxy, membered ring trifluoromethyl, and alkyl substituted byan optionally substituted 5- or 6- membered ring Fragment (C*), R^(a) =H, Category (iii) moiety, e.g. n = 1, 2, 3, or 4. Rz* = category (i) or(ii) having a structure R⁴ = selected from Cl, F, corresponding to thehydroxy, methyl, methoxy, category (iii) structure of trifluoromethyl,and alkyl Fragment (D1*) substituted by an optionally substituted 5- or6- membered ring Fragment (C*), R^(a) = H, Category (iii) moiety, e.g. n= 1, 2, 3, or 4. Rz* = category (i) or (ii) having a structure R⁴ =selected from Cl, F, corresponding to the hydroxy, methyl, methoxy,category (iii) structure of trifluoromethyl, and alkyl Fragment (D2*)substituted by an optionally substituted 5- or 6- membered ring Fragment(C*), R^(a) = H, Category (iii) moiety, e.g. n = 1, 2, 3, or 4. Rz* =category (i) or (ii) having a structure R⁴ = selected from Cl, F,corresponding to the hydroxy, methyl, methoxy, category (iii) structureof trifluoromethyl, and alkyl Fragment (E1*). substituted by anoptionally substituted 5- or 6- membered ring Fragment (C*), R^(a) = H,Category (iii) moiety, e.g. n = 1, 2, 3, or 4. Rz* = category (i) or(ii) having a structure R⁴ = selected from Cl, F, corresponding to thehydroxy, methyl, methoxy, category (iii) structure of trifluoromethyl,and alkyl Fragment (E2*). substituted by an optionally substituted 5- or6- membered ring Fragment (C*), R^(a) = H, Category (iii) moiety, e.g. n= 1, 2, 3, or 4. Rz* = category (i) or (ii) having a structure R⁴ =selected from Cl, F, corresponding to the hydroxy, methyl, methoxy,category (iii) structure of trifluoromethyl, and alkyl Fragment (E3).substituted by an optionally substituted 5- or 6- membered ring Fragment(C*), R^(a) = H, Category (iii) moiety, e.g. n = 1, 2, 3, or 4. Rz* =category (i) or (ii) having a structure R⁴ = selected from Cl, F,corresponding to the hydroxy, methyl, methoxy, category (iii) structureof trifluoromethyl, and alkyl Fragment (E4). substituted by anoptionally substituted 5- or 6- membered ring Fragment (C*), R^(a) = H,Category (iii) moiety, e.g. n = 1, 2, 3, or 4. Rz* = category (i) or(ii) having a structure R⁴ = selected from Cl, F, corresponding to thehydroxy, methyl, methoxy, category (iii) structure of trifluoromethyl,and alkyl Fragment (F*). substituted by an optionally substituted 5- or6- membered ring Fragment (C*), R^(a) = H, C₁-C₄ alkyl or C₁-C₄ alkyl n= 1, 2, 3, or 4. Rz* = category (iii) substituted by an optionally R⁴ =selected from Cl, F, substituted 5- or 6- hydroxy, methyl, methoxy,membered ring trifluoromethyl, and alkyl substituted by an optionallysubstituted 5- or 6- membered ring Fragment (D1*) C₁-C₄ alkyl or C₁-C₄alkyl n = 1, 2, 3, or 4. substituted by an optionally R⁴ = selected fromCl, F, substituted 5- or 6- hydroxy, methyl, methoxy, membered ringtrifluoromethyl, and alkyl substituted by an optionally substituted 5-or 6- membered ring Fragment (D2*) C₁-C₄ alkyl or C₁-C₄ alkyl n = 1, 2,3, or 4. substituted by an optionally R⁴ = selected from Cl, F,substituted 5- or 6- hydroxy, methyl, methoxy, membered ringtrifluoromethyl, and alkyl substituted by an optionally substituted 5-or 6- membered ring Fragment (E1*) C₁-C₄ alkyl or C₁-C₄ alkyl n = 1, 2,3, or 4. substituted by an optionally R⁴ = selected from Cl, F,substituted 5- or 6- hydroxy, methyl, methoxy, membered ringtrifluoromethyl, and alkyl substituted by an optionally substituted 5-or 6- membered ring Fragment (E2*) C₁-C₄ alkyl or C₁-C₄ alkyl n = 1, 2,3, or 4. substituted by an optionally R⁴ = selected from Cl, F,substituted 5- or 6- hydroxy, methyl, methoxy, membered ringtrifluoromethyl, and alkyl substituted by an optionally substituted 5-or 6- membered ring Fragment (E3) C₁-C₄ alkyl or C₁-C₄ alkyl n = 1, 2,3, or 4. substituted by an optionally R⁴ = selected from Cl, F,substituted 5- or 6- hydroxy, methyl, methoxy, membered ringtrifluoromethyl, and alkyl substituted by an optionally substituted 5-or 6- membered ring Fragment (E4) C₁-C₄ alkyl or C₁-C₄ alkyl n = 1, 2,3, or 4. substituted by an optionally R⁴ = selected from Cl, F,substituted 5- or 6- hydroxy, methyl, methoxy, membered ringtrifluoromethyl, and alkyl substituted by an optionally substituted 5-or 6- membered ring Fragment (F*) C₁-C₄ alkyl or C₁-C₄ alkyl n = 1, 2,3, or 4. substituted by an optionally R⁴ = selected from Cl, F,substituted 5- or 6- hydroxy, methyl, methoxy, membered ringtrifluoromethyl, and alkyl substituted by an optionally substituted 5-or 6- membered ring Fragment (C*), R^(a) H n = 1, 2, 3, or 4. typically= H, R⁴ = selected from Cl, F, Rz* = category (iii) hydroxy, methyl,methoxy, trifluoromethyl, and alkyl substituted by an optionallysubstituted 5- or 6- membered ring Fragment (D1*); R^(a) H n = 1, 2, 3,or 4. typically = H, R⁴ = selected from Cl, F, hydroxy, methyl, methoxy,trifluoromethyl, and alkyl substituted by an optionally substituted 5-or 6- membered ring Fragment (D2*); R^(a) H n = 1, 2, 3, or 4. typically= H, R⁴ = selected from Cl, F, hydroxy, methyl, methoxy,trifluoromethyl, and alkyl substituted by an optionally substituted 5-or 6- membered ring Fragment (E1*); R^(a) H n = 1, 2, 3, or 4. typically= H, R⁴ = selected from Cl, F, hydroxy, methyl, methoxy,trifluoromethyl, and alkyl substituted by an optionally substituted 5-or 6- membered ring Fragment (E2*); R^(a) H n = 1, 2, 3, or 4. typically= H, R⁴ = selected from Cl, F, hydroxy, methyl, methoxy,trifluoromethyl, and alkyl substituted by an optionally substituted 5-or 6- membered ring Fragment (F*) H n = 1, 2, 3, or 4. R⁴ = selectedfrom Cl, F, hydroxy, methyl, methoxy, trifluoromethyl, and alkylsubstituted by an optionally substituted 5- or 6- membered ring Fragment(A*) H, C₁-C₄ alkyl or C₁-C₄ alkyl R⁴ is Fragment substituted by anoptionally (L), (M) or (N). substituted 5- or 6- membered ring Fragment(B*) H, C₁-C₄ alkyl or C₁-C₄ alkyl R⁴ is Fragment substituted by anoptionally (L), (M) or (N). substituted 5- or 6- membered ring Fragment(C*) H, C₁-C₄ alkyl or C₁-C₄ alkyl R⁴ is Fragment substituted by anoptionally (L), (M) or (N). substituted 5- or 6- membered ring Fragment(C*), R^(a) = H, H, C₁-C₄ alkyl or C₁-C₄ alkyl R⁴ is Fragment Rz* =category (i) or (ii) substituted by an optionally (L), (M) or (N).substituted 5- or 6- membered ring Fragment (C*), R^(a) = H, Category(iii) moiety, e.g. R⁴ is Fragment Rz* = category (i) or (ii) having astructure (L), (M) or (N). corresponding to the category (iii) structureof Fragment (D1*) Fragment (C*), R^(a) = H, Category (iii) moiety, e.g.R⁴ is Fragment Rz* = category (i) or (ii) having a structure (L), (M) or(N). corresponding to the category (iii) structure of Fragment (D2*)Fragment (C*), R^(a) = H, Category (iii) moiety, e.g. R⁴ is Fragment Rz*= category (i) or (ii) having a structure (L), (M) or (N). correspondingto the category (iii) structure of Fragment (E1*). Fragment (C*), R^(a)= H, Category (iii) moiety, e.g. R⁴ is Fragment Rz* = category (i) or(ii) having a structure (L), (M) or (N). corresponding to the category(iii) structure of Fragment (E2*). Fragment (C*), R^(a) = H, Category(iii) moiety, e.g. R⁴ is Fragment Rz* = category (i) or (ii) having astructure (L), (M) or (N). corresponding to the category (iii) structureof Fragment (E3). Fragment (C*), R^(a) = H, Category (iii) moiety, e.g.R⁴ is Fragment Rz* = category (i) or (ii) having a structure (L), (M) or(N). corresponding to the category (iii) structure of Fragment (E4).Fragment (C*), R^(a) = H, Category (iii) moiety, e.g. R⁴ is Fragment Rz*= category (i) or (ii) having a structure (L), (M) or (N). correspondingto the category (iii) structure of Fragment (F*). Fragment (C*), R^(a) =H, C₁-C₄ alkyl or C₁-C₄ alkyl R⁴ is Fragment Rz* = category (iii)substituted by an optionally (L), (M) or (N). substituted 5- or 6-membered ring Fragment (D1*) C₁-C₄ alkyl or C₁-C₄ alkyl R⁴ is Fragmentsubstituted by an optionally (L), (M) or (N). substituted 5- or 6-membered ring Fragment (D2*) C₁-C₄ alkyl or C₁-C₄ alkyl R⁴ is Fragmentsubstituted by an optionally (L), (M) or (N). substituted 5- or 6-membered ring Fragment (E1*) C₁-C₄ alkyl or C₁-C₄ alkyl R⁴ is Fragmentsubstituted by an optionally (L), (M) or (N). substituted 5- or 6-membered ring Fragment (E2*) C₁-C₄ alkyl or C₁-C₄ alkyl R⁴ is Fragmentsubstituted by an optionally (L), (M) or (N). substituted 5- or 6-membered ring Fragment (E3) C₁-C₄ alkyl or C₁-C₄ alkyl R⁴ is Fragmentsubstituted by an optionally (L), (M) or (N). substituted 5- or 6-membered ring Fragment (E4) C₁-C₄ alkyl or C₁-C₄ alkyl R⁴ is Fragmentsubstituted by an optionally (L), (M) or (N). substituted 5- or 6-membered ring Fragment (F*) C₁-C₄ alkyl or C₁-C₄ alkyl R⁴ is Fragmentsubstituted by an optionally (L), (M) or (N). substituted 5- or 6-membered ring Fragment (C*), R^(a) H R⁴ is Fragment typically = H, (L),(M) or (N). Rz* = category (iii) Fragment (D1*); R^(a) H R⁴ is Fragmenttypically = H, (L), (M) or (N). Fragment (D2*); R^(a) H R⁴ is Fragmenttypically = H, (L), (M) or (N). Fragment (E1*); R^(a) H R⁴ is Fragmenttypically = H, (L), (M) or (N). Fragment (E2*); R^(a) H R⁴ is Fragmenttypically = H, (L), (M) or (N). Fragment (E3); R^(a) H R⁴ is Fragmenttypically = H, (L), (M) or (N). Fragment (E4); R^(a) H R⁴ is Fragmenttypically = H, (L), (M) or (N). Fragment (F*) H R⁴ is Fragment (L), (M)or (N).

When R³ is an optionally substituted ring, substituents are as describedpreviously, e.g. methyl, ethyl, methoxy, trifluoromethyl, amino orhydroxy.

Each row of the above table provides support for an individual patentclaim, presented by itself or with one or more other claims, eachcorresponding to a respective row of the table. The previous textprovides support for claims dependent on such claims in describingsub-classes of the respective features or feature combinations of eachrow. For each row in the Table, a patent claim or claims may be writtento protect individually a sub-class or sub-classes of the subject matterrepresented by the row.

It will be understood from the aforegoing that a sub-set of theCompounds of Formula (I*) are of the following Formulae (VI*) and(VII*):

In Formulae (VI*) and (VII*), it is often the case that two of X, Y andZ are N and that R³ and R² are H, e.g. in many compounds X is CH, Y andZ are N and R² is H. Alternatively, all of X, Y and Z are N and R² is H.Ring A is typically phenyl or a wholly or partially hydrogenatedanalogue thereof. Alternatively it may be a heterocycle, typically ofsix members, e.g. pyridine or pyrimidine. Integer m may be 0, 1 or 2,e.g. 1. In some cases there are one or more R^(b) moieties which are For Cl, as previously described, e.g. the only R^(b) moieties may be oneor two moieties selected from F and Cl.

Accordingly, Formulae (VI*) and (VII*) encompass the followingsub-classes, amongst others:

-   -   1) One of X, Y and Z are N, R¹⁵ and R² are H, ring A is phenyl        or a wholly or partially hydrogenated analogue thereof, m is 0,        1 or 2, e.g. 1;    -   2) One of X, Y and Z are N, R¹⁵ and R² are H, ring A is a        heterocycle, typically of six members, e.g. pyridine or        pyrimidine, m is 0, 1 or 2, e.g. 1;    -   3) Two of X, Y and Z are N, R¹⁵ and R² are H, ring A is phenyl        or a wholly or partially hydrogenated analogue thereof, m is 0,        1 or 2, e.g. 1;    -   4) Two of X, Y and Z are N, R¹⁵ and R² are H, ring A is a        heterocycle, typically of six members, e.g. pyridine or        pyrimidine, m is 0, 1 or 2, e.g. 1;    -   5) All of X, Y and Z are N, R² is H, ring A is phenyl or a        wholly or partially hydrogenated analogue thereof, m is 0, 1 or        2, e.g. 1;    -   6) All of X, Y and Z are N, R² is H, ring A is a heterocycle,        typically of six members, e.g. pyridine or pyrimidine, m is 0, 1        or 2, e.g. 1;    -   7) X is CH, Y and Z are N, R² is H, ring A is phenyl or a wholly        or partially hydrogenated analogue thereof, m is 0, 1 or 2, e.g.        1;    -   8) X is CH, Y and Z are N, R² is H, ring A is a heterocycle,        typically of six members, e.g. pyridine or pyrimidine, m is 0, 1        or 2, e.g. 1.

In some instances of sub-classes 1), 2), 3) 4), 5) and 6) there are oneor more R^(b) moieties which are F or Cl, as previously described, e.g.the only R^(b) moieties may be one or two moieties selected from F andCl.

More commonly, ring A is substituted by one or two R^(b) moieties (andnormally a single R^(b) moiety) comprising -L²-RING* or -L²-NR^(b)R^(d),and optionally other substituents (e.g. numbering 1, 2 or 3) selectedfrom e.g. halogen; hydroxy; protected hydroxy for exampletrialkylsilylhydroxy; amino; amidino; guanidino; hydroxyguanidino;formamidino; isothioureido; ureido; mercapto; C(O)H or other lower acyl;lower acyloxy; carboxy; sulfo; sulfamoyl; carbamoyl; cyano; azo; nitro;which substituents are in turn optionally substituted on at least oneheteroatom by one or, where possible, more C₁, C₂, C₃ or C₄ alkylgroups. Particular additional substituents on ring A are halogen, loweralkyl (e.g. methyl), lower alkoxy (e.g. methoxy), hydroxy, amino ortrifluoromethyl.

Also to be mentioned therefore are compounds of the following formulae(VIII*), (IX*), (X*) and (XI*):

where

-   -   L²NR^(c)R^(d) is in particular -Pip, -Morph, —OCH₂Pip,        —OCH₂-Morph, —OCH₂CH₂Pip, —OCH₂CH₂-Morph, —OCH₂CH₂CH₂Pip,        —OCH₂CH₂CH₂-Morph, —CH₂Pip, —CH₂-Morph, —CH₂CH₂Pip,        —CH₂CH₂-Morph, —CH₂CH₂CH₂Pip, and —CH₂CH₂CH₂-Morph, or is        —C(O)Pip or —C(O)Morph (or of course these heterocycles are        replaced by another described herein, or in other embodiments        R^(c) and R^(d) form a non-cyclic structure as previously        described);    -   L²RING* is in particular -RING*, —OCH₂RING*, —OCH₂CH₂RING*,        —OCH₂CH₂CH₂RING*, —CH₂RING*, —CH₂CH₂RING*, —CH₂CH₂CH₂RING*, or        is —C(O)RING*, where RING* is in particular pyrrolidine,        piperidine, piperazine or morpholine, or it may be another RING*        moiety disclosed herein;    -   R³ is as previously described and is particularly but not        necessarily H;    -   R⁴ is as previously described and is particularly but not        necessarily selected from Cl, F, hydroxy, methyl, methoxy and        trifluoromethyl;        -   L¹ is in particular —NR^(a)CO— and —CONR^(a)—;        -   R¹⁶ is as previously described but is in particular            substituted alkyl, where the substitutents are in particular            fluorine and piperizine,    -   m is 0, 1, 2, 3, 4 or 5, e.g. is 1 or 2;    -   n is 0, 1, 2, 3, 4 or 5, e.g. is 1, 2, 3, or 4.

In embodiments, RING* or a heterocycle formed by L²NR^(c)R^(d) issubstituted by 1, 2, 3, 4 or 5 substituents, e.g. 1 or 2 substituents,selected from alkyl, alkoxy, alkanoyl, alkanoyloxy, haloalkyl, amino,mono- or di-alkylamino, cyano, halogen, hydroxy or protected hydroxy,wherein alkyl or the alkyl part of alkoxy and alkanoyl(oxy) has 1, 2, 3or 4 carbon atoms; exemplary substituents in this case are methyl,ethyl, methoxy, ethoxy, acetyl, trifluoromethyl, cyano, F, Cl and OH.N-alkyl substituted piperazine or piperadine are exemplary, as are RING*moieties as a class substituted by one or two substituents or more,selected from alkyl and haloalkyl (e.g. trifluoromethyl). As analternative to substitution, there may be no substitution.

Another embodiment comprises compounds of formula (XXI*):

where Rz*¹ and Rz*² are selected from hydrogen and straight chain orbranched alkyl having 1, 2, 3 or 4 carbon atoms, e.g. methyl or ethyl.In embodiments, one of Rz*¹ and Rz*² is hydrogen and more particularlyboth are hydrogen. It is often the case that X is CH, Y and Z are N andR² is H. Particular classes of compounds are of formulae (XXI*),(XXII*), (XXIII*) and (XXIV*):

where Rz*¹ and Rz*² are selected from hydrogen and straight chain orbranched alkyl having 1, 2, 3 or 4 carbon atoms, e.g. methyl or ethyl,and L²NR^(c)R^(d), L²RING*, R³ and R⁴ are as described in relation toformulae (IV*)-(VII*).

The invention includes classes of compounds which correspond to Formulae(IV*), (V*), (VI*), (VII*), (XXI*), (XXII*), (XXIII*) and (XXIV*) inwhich the pyrimidine ring is replaced by a triazine ring

Substituents

The following definitions apply to the compounds of the invention asappropriate and expedient and if not mentioned otherwise.

“Substituted”, wherever used for a moiety, means that one or morehydrogen atoms in the respective moiety, especially up to 5, moreespecially 1, 2 or 3 of the hydrogen atoms are replaced independently ofeach other by the corresponding number of substituents which preferablyare independently selected from the group consisting of lower alkyl, forexample methyl, ethyl or propyl, halo-lower alkyl, for exampletrifluoromethyl, C₆-C₁₆-aryl, especially phenyl pyridine.

-   -   C₆-C₁₆-aryl is unsubstituted or substituted by one or more,        especially 1, 2 or 3 moieties selected from, for example, lower        alkyl, halogen, carboxy, lower alkoxycarbonyl, hydroxy,        etherified or esterified hydroxy, lower alkoxy, phenyl-lower        alkoxy, lower alkanoyloxy, lower alkanoyl, amino, mono- or        di-substituted amino, halo, halo-lower alkyl, e.g.        trifluoromethyl, sulfo, sulfamoyl, carbamoyl, N-mono substituted        or N,N-disubstituted carbamoyl, N-lower alkyl-carbamoyl,        N-(hydroxy-lower alkyl)-carbamoyl, such as        N-(2-hydroxyethyl)-carbamoyl, cyano, cyano-lower alkyl and        nitro;    -   Substituents also include hydroxy, C₃-C₁₀-cycloalkyl, especially        cyclopropyl or cyclohexyl, hydroxy-C₃-C₈-cycloalkyl, such as        hydroxy-cyclohexyl, heterocyclyl with 5 or 6 ring atoms and 1 to        3 ring heteroatoms selected from O, N and S, especially        piperidinyl, especially piperidin-1-yl, piperazinyl, especially        piperazin-1-yl, morpholinyl, especially morpholin-1-yl, hydroxy,        lower alkoxy, for example methoxy, halo-lower alkoxy, especially        2,2,2-trifluoroethoxy, phenyl-lower alkoxy, amino-lower alkoxy,        such as 2-eminoethoxy; lower alkanoyloxy, hydroxy-lower alkyl,        such as hydroxymethyl or 2-hydroxyethyl, amino, mono- or        di-substituted amino, carbamoyl-lower alkoxy, N-lower        alkylcarbamoyl-lower alkoxy or N,N-di-lower alkylcarbamoyl-lower        alkoxy, amidino, ureido, mercapto, N-hydroxy-amidino, guanidino,        amidino-lower alkyl, such as 2-amidinoethyl,        N-hydroxyamidino-lower alkyl, such as N-hydroxy-amidino-methyl        or -2-ethyl, halogen, for example fluoro, chloro, bromo or iodo,        carboxy, esterified carboxy, lower alkoxycarbonyl, phenyl-,        naphthyl- or fluorenyl-lower alkoxycarbonyl, such as        benzyloxycarbonyl, benzoyl, lower alkanoyl, sulfo, lower        alkanesul-fonyl, for example methanesulfonyl (CH₃—S(O)₂—), lower        alkylthio, phenylthio, phenyl-lower alkylthio, lower        alkylphenylthio, lower alkylsulfinyl, phenylsulfinyl,        phenyl-lower alkylsulfinyl, lower alkylphenylsulfinyl,        halogen-lower alkylmercapto, halogen-lower alkylsulfonyl, such        as especially trifluoromethanesulfonyl, dihydroxybora (—B(OH)₂),        phosphono (—P(═O)(OH)₂), hydroxy-lower alkoxy phosphoryl or        di-lower alkoxyphosphoryl, carbamoyl, mono- or di-lower        alkylcarbamoyl, mono- or di-(hydroxy-lower alkyl)-carbamoyl,        sulfamoyl, mono- or di-lower alkylaminosulfonyl, nitro,        cyano-lower alkyl, such as cyanomethyl, and cyano, lower        alkenyl, lower alkynyl.

It goes without saying that substituents are only at positions wherethey are chemically pos-sible, the person skilled in the art being ableto decide (either experimentally or theoretically) without inappropriateeffort which substitutions are possible and which are not. For example,amino or hydroxy groups with free hydrogen may be unstable if bound tocarbon atoms with unsaturated (e.g. olefinic) bonds. Additionally, itwill of course be understood that the substituents as listed above maythemselves be substituted by any substituent, subject to theaforementioned restriction to appropriate substitutions as recognised bythe skilled man.

Other Definitions

The general terms used hereinbefore and hereinafter preferably havewithin the context of this disclosure the following meanings, unlessotherwise indicated:

The prefix “lower” denotes a radical having up to and including amaximum of 7 in-chain atoms, especially up to and including a maximum of4 in-chain atoms. Particular classes of alkyl and aliphatic comprise 1,2, 3 or 4 carbon atoms. The radicals in question being either linear orbranched with single or multiple branching.

Lower alkyl is preferably alkyl with from and including 1 up to andincluding 7 carbon atoms, preferably 1, 2, 3 or 4 carbon atoms, and islinear or branched; for example, lower alkyl is butyl, such as n-butyl,sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl,ethyl or methyl. Exemplary lower alkyl is methyl, propyl or tert-butyl.

Where the plural form is used for compounds, salts, and the like, thisis taken to mean also a single compound, salt, or the like.

Any asymmetric carbon atoms may be present in the (R)-, (S)- or(R,S)-configuration, preferably in the (R)- or (S)-configuration.Radicals having any unsaturation are present in cis-, trans- or (cis,trans) form. The compounds may thus be present as mixtures of isomers oras pure isomers, preferably as enantiomer-pure diastereomers.

The invention relates also to possible tautomers of the disclosedcompounds.

In view of the close relationship between the heteroaryl aryl ureas infree form and in the form of their salts, including those salts that canbe used as intermediates, for example in the purification oridentification of the novel compounds, tautomers or tautomeric mixturesand their salts, any reference hereinbefore and hereinafter to thesecompounds, is to be understood as referring also to the correspondingtautomers of these compounds, or salts of any of these, as appropriateand expedient and if not mentioned otherwise.

Tautomers can, e.g., be present in cases where amino or hydroxy, eachwith a least one bound hydrogen, are bound to carbon atoms that arebound to adjacent atoms by double bonds (e.g. keto-enol or imine-enaminetautomerism).

Where “a compound . . . , a tautomer thereof; or a salt thereof” or thelike is mentioned, this means “a compound . . . , a tautomer thereof, ora salt of the compound or the tautomer”.

By acyl is meant an organic radical corresponding to the residue of, forexample, an organic acid from which the hydroxyl group has been removed,i.e., a radical having the formula R—C(O)—, where R may in particular bealiphatic or substituted aliphatic, or it may for example be asubstituted or unsubstituted mono- or bi-cyclic ring. Thus, R may beselected from lower C₁-C₆ alkyl, C₃-C₇ cycloalkyl, phenyl, benzyl orphenethyl group. Amongst others. Exemplary acyl is alkyl-carbonyl.Examples of acyl groups, include, but are not limited to, formyl,acetyl, propionyl and butyryl. Lower acyl is for example formyl or loweralkylcarbonyl, in particular acetyl.

Aliphatic may have up to 20, e.g up to 12, carbon atoms and is linear orbranched one or more times; preferred is lower aliphatic, especiallyC₁-C₄-aliphatic. Aliphatic moieties may be alkyl, alkenyl or alkynyl;alkenyl and alkynyl may contain one or more, e.g. one or two,unsaturated carbon-carbon bonds.

Alkyl may have up to 20, e.g up to 12, carbon atoms and is linear orbranched one or more times; preferred is lower alkyl, especiallyC₁-C₄-alkyl, in particular methyl, ethyl or i-propyl or t-butyl. Wherealkyl may be substituted by one or more substituents independentlyselected from those mentioned above under the title “Substituents”.Unsubstituted alkyl, preferably lower alkyl, is especially preferred.The term alkyl also encompasses cycloalkyl as defined further below:

Alkyl may be optionally interrupted by one or more in-chain heteroatoms,for example —O—, thus forming, for example, an ether linkage.

Cycloalkyl is preferably C₃-C₁₀-cycloalkyl, especially cyclopropyl,dimethylcyclopropyl, cyclo-butyl, cyclopentyl, cyclohexyl orcycloheptyl, cycloalkyl being unsubstituted or substituted by one ormore, especially 1, 2 or 3, substituents independently selected from thegroup consisting of the substituents defined above under the title“Substituents”.

Alkenyl may have one or more double bonds and preferably has 2 to 20,more preferably up to 12, carbon atoms; it is linear or branched one ormore times (as far as possible in view of the number of carbon atoms).Preferred is C₂-C₇-alkenyl, especially C₃ or C₄-alkenyl, such as allylor crotyl. Alkenyl can be unsubstituted or substituted, especially byone or more, more especially up to three, of the substituents mentionedabove under “the title “Substituents”. Substituents such as amino orhydroxy (with free dissociable hydrogen) preferably are not bound tocarbon atoms that participate at a double bond, and also othersubstituents that are not sufficiently stable are preferably excluded.Unsubstituted alkenyl, in particular C₂-C₇-alkenyl, is preferred.

Alkynyl is preferably a moiety with one or more triple bonds andpreferably has 2 to 20, more preferably up to 12, carbon atoms; it islinear of branched one or more times (as far as pos-sible in view of thenumber of carbon atoms). Preferred is C₂-C₇-alkynyl, especially C₃ orC₄-alkynyl, such as ethinyl or propin-2-yl. Alkynyl can be unsubstitutedor substituted, especially by one or more, more especially up to three,of the substituents mentioned above under the title “Substituents”.Substituents such as amino or hydroxy (with free dissociable hydrogen)preferably are not bound to carbon atoms that participate at a triplebond, and also other substituents that are not sufficiently stable arepreferably excluded. Unsubstituted alkynyl, in particular C₂-C₇-alkynyl,is preferred.

An aryl group is an aromatic radical and may be heterocyclic orcarbocyclic. Preferably, aryl is carbocyclic and is bound to themolecule via a bond located at an aromatic ring carbon atom of theradical (or optionally bound via a linking group, such as —O— or —CH₂—).Preferably aryl has a ring system of not more than 16 carbon atoms andis preferably mono- bi- or tri-cyclic and may be fully or partiallysubstituted, for example substituted by at least two substituents.Preferably, aryl is selected from phenyl, naphthyl, indenyl, azulenyland anthryl, and is preferably in each case unsubstituted or loweralkyl, especially methyl, ethyl or n-propyl, halo (especially fluoro,chloro, bromo or iodo), halo-lower alkyl (especially trifluoromethyl),hydroxy, lower alkoxy (especially methoxy), halo-lower alkoxy(especially 2,2,2-trifluoroethoxy), amino-lower alkoxy (especially2-amino-ethoxy), lower alkyl (especially methyl or ethyl) carbamoyl,N-(hydroxy-lower alkyl)-carbamoyl (especiallyN-(2-hydroxyethyl)-carbamoyl) and/or sulfamoyl-substituted aryl,especially a corresponding substituted or unsubstituted phenyl. Also,heterocyclic groups can be mentioned here, as defined below.

Any carbocyclic group especially comprises 3, 4, 5, 6 or 7 in ringcarbon atoms and may be aromatic (aryl) or non aromatic. Where thecarbocycle is non-aromatic, it may be saturated or unsaturated.Especially preferred carbocycles are phenyl, cyclohexyl and cyclopentyl.

Heterocyclyl (or heterocyclic group) is preferably a heterocyclicradical that is unsaturated, saturated or partially saturated and ispreferably a monocyclic or in a broader aspect of the invention bicyclicor tricyclic ring; has 3 to 24, more preferably 4 to 16 ring atoms.Heterocycles may contain one or more, preferably one to four, especiallyone or two ring-forming heteroatoms selected from the group consistingof nitrogen, oxygen and sulfur, the ring preferably having 4 to 12,especially 5 to 7 ring atoms. Heterocycles may be unsubstituted orsubstituted by one or more, especially 1 to 3, substituentsindependently selected from the group consisting of the substituentsdefined above under the tile “Substituents”. Heterocycle especially is aradical selected from the group consisting of oxiranyl, azirinyl,1,2-oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl, pyranyl,thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, chromenyl,2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl,imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl,pyranyol, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl,pyridyl, pyr-azinyl, pyrimidinyl, piperidyl, especially piperidin-1-yl,piperazinyl, especially piperazin-1-yl, pyridazinyl, morpholinyl,especially morpholino, thiomorpholinyl, especially thiomorpholino,indolizinyl, isoindolyl, 3H-indolyl, indolyl, benzimidazolyl, cumaryl,indazolyl, triazolyl, tetrazolyl, purinyl, 4H-quinolizinyl, isoquinolyl,quinolyl, tetrahydroquinolyl, tetrahydroiso-quinolyl, decahydroquinolyl,octahydroisoquinolyl, benzofuranyl, dibenzofuranyl, benzothiophenyl,dibenzothiophenyl, phthalazinyl, naphthyridinyl, quinoxalyl,quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phen-anthrolinyl,furazanyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromenyl,isochromanyl and chromanyl, each of these radicals being unsubstitutedor substituted by one to two radicals selected from the group consistingof lower alkyl, especially methyl or tert-butyl, lower alkoxy,especially methoxy, and halo, especially bromo or chloro. Unsubstitutedheterocyclyl, especially piperidyl, piperazinyl, thiomorpholino ormorpholino, is preferred.

Any heterocyclic group especially comprises five or six in-chain atomsof which at least one is a heteroatom selected from N, O or S.Especially preferred heterocycles are pyridine, pyrrolidine, piperidineand morpholine.

Mono- or disubstituted amino may be an amino group substituted by one ormore of the substituents as listed under the heading “Substituents” andmay form a secondary or tertiary amine group and/or is especially anamino and having the formula NR^(k) ₂, NR^(k)OH, NR^(k)COR^(k) (e.g.NHCO-alkyl), NR^(k)COOR^(k) (e.g NR^(k)COO-alkyl), NR^(k)C(NR^(k))H(e.g. NHC(NH)H), NR^(k)C(NR^(k))NR^(k)OH (e.g. NHC(NH)NHOH),NR^(k)C(NR^(k))NR^(k)CN, (e.g. NHC(NH)NHCN),NR^(k)C(NR^(k))NR^(k)COR^(k), (e.g. NHC(NH)NHCOR^(k)),NR^(k)C(NR^(k))NR^(k)R², (e.g. NHC(NH)NHR^(k)),N(COOR^(k))C(NH₂)═NCOOR^(k), (e.g. N(COOR^(k))C(NH₂)═NCOOR^(k)), where

each R^(k) is independently selected from the substituents as listedunder the heading “Substituents” and may especially be selected fromhydrogen, hydroxy, alkyl, substituted alkyl, lower alkyl, such asmethyl; hydroxy-lower alkyl, such as 2-hydroxyethyl; halo-lower alkyl,lower alkoxy lower alkyl, such as methoxy ethyl; alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substitutedcycloalkyl, heteroaryl, heterocyclyl, lower alkanoyl, such as acetyl;benzoyl; substituted benzoyl, phenyl, phenyl-lower alkyl, such as benzylor 2-phenylethyl.

Any R^(k) group may be substituted by the substituents as defined underthe heading “Substituents” and the substituents may be selected from,preferably one or two of, nitro, amino, halogen, hydroxy, cyano,carboxy, lower alkoxycarbonyl, lower alkanoyl, and carbamoyl; andphenyl-lower alkoxycarbonyl.

As such, exemplary substituted amino groups are N-lower alkylamino, suchas N-methylamino, N,N-di-lower alkylamino, N-lower alkylaminoamino-loweralkyl, such as aminomethyl or 2-aminoethyl, hydroxy-lower alkylamino,such as 2-hydroxyethylamino or 2-hydroxypropyl, lower alkoxy loweralkyl, such as methoxy ethyl, phenyl-lower alkylamino, such asbenzylamino, N,N-di-lower alkylamino, N-phenyl-lower alkyl-N-loweralkylamino, N,N-di-lower alkylphenylamino, lower alkanoylamino, such asacetylamino, benzoylamino, phenyl-lower alkoxycarbonylamino, carbamoylor aminocarbonylamino, amino-lower alkyl-oxyphenyl-amino,sulfamoylphenylamino, [N-(hydroxy-lower alkyl)-carbamoyl]-phenylamino.An example of a substituted amino is an amino substituted by a4-substituted cyclohexyl, for example cyclohexan-4-ol.

Disubstituted amino may also be lower alkylene-amino, e.g. pyrrolidino,2-oxopyrrolidino or piperidino; lower oxaalkylene-amino, e.g.morpholino, or lower azaalkylene-amino, e.g. piperazino or N-substitutedpiperazino, such as N-methylpiperazine, N-methoxycarbonylpiperazino,N-mono substituted or N,N-disubstituted carbamoyl, N-loweralkyl-carbamoyl or N-(hydroxy-lower alkyl)-carbamoyl, such asN-(2-hydroxyethyl)-carbamoyl. It is also contemplated that analkanoylamino extends to a carbamate, such as carbamic acid methylester.

Halogen (halo) is especially fluorine, chlorine, bromine, or iodine,especially fluorine, chlorine, or bromine most especially chlorine orfluorine.

Etherified hydroxy is especially C₈-C₂₀alkyloxy, such as n-decyloxy,lower alkoxy (preferred), such as methoxy, ethoxy, isopropyloxy, ortert-butyloxy, phenyl-lower alkoxy, such as benzyloxy, phenyloxy,halogen-lower alkoxy, such as trifluoromethoxy, 2,2,2-trifluoroethoxy or1,1,2,2-tetrafluoroethoxy, or lower alkoxy which is substituted by mono-or bicyclic hetero-aryl comprising one or two nitrogen atoms, preferablylower alkoxy which is substituted by imidazolyl, such as1H-imidazol-1-yl, pyrrolyl, benzimidazolyl, such as 1-benzimidazolyl,pyridyl, especially 2-, 3- or 4-pyridyl, pyrimidinyl, especially2-pyrimidinyl, pyrazinyl, isoquinolinyl, especially 3-isoquinolinyl,quinolinyl, indolyl or thiazolyl.

Esterified hydroxy is especially lower alkanoyloxy, benzoyloxy, loweralkoxycarbonyloxy, such as tert-butoxycarbonyloxy, or phenyl-loweralkoxycarbonyloxy, such as benzyloxycarbonyloxy.

Esterified carboxy is especially lower alkoxycarbonyl, such astert-butoxycarbonyl, iso-propoxycarbonyl, methoxycarbonyl orethoxycarbonyl, phenyl-lower alkoxycarbonyl, or phenyloxycarbonyl.

Alkanoyl is alkylcarbonyl, especially lower alkanoyl, e.g. acetyl. Thealkyl part of the alkanoyl group may be substituted to form a moietyR¹⁰.

N-Mono- or N,N-disubstituted carbamoyl is especially substituted by oneor two substituents independently selected from lower alkyl,phenyl-lower alkyl and hydroxy-lower alkyl, or lower alkylene, oxa-loweralkylene or aza-lower alkylene optionally substituted at the terminalnitrogen atom.

Salts are especially the pharmaceutically acceptable salts of compoundsof Formula (I) (or exemplary formula thereof), especially if they areforming salt-forming groups.

Salt-forming groups are groups or radicals having basic or acidicproperties. Compounds ha-ving at least one basic group or at least onebasic radical, for example amino, a secondary amino group not forming apeptide bond or a pyridyl radical, may form acid addition salts, forexample with inorganic acids, such as hydrochloric acid, sulfuric acidor a phosphoric acid, or with suitable organic carboxylic or sulfonicacids, for example aliphatic mono- or di-carboxylic acids, such astrifluoroacetic acid, acetic acid, propionic acid, glycolic acid,succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malicacid, tartaric acid, citric acid or oxalic acid, or amino acids such asarginine or lysine, aromatic carboxylic acids, such as benzoic acid,2-phenoxy-benzoic acid, 2-acetoxy-benzoic acid, salicylic acid,4-aminosalicylic acid, aromatic-aliphatic carboxylic acids, such asmandelic acid or cinnamic acid, heteroaromatic carboxylic acids, such asnicotinic acid or isonicotinic acid, aliphatic sulfonic acids, such asmethane-, ethane- or 2-hydroxyethanesulfonic acid, or aromatic sulfonicacids, for example benzene-, p-toluene- or naphthalene-2-sulfonic acid.When several basic groups are present mono- or poly-acid addition saltsmay be formed.

Compounds having acidic groups, a carboxy group or a phenolic hydroxygroup, may form metal or ammonium salts, such as alkali metal oralkaline earth metal salts, for example so-dium, potassium, magnesium orcalcium salts, or ammonium salts with ammonia or suitable organicamines, such as tertiary monoamines, for example triethylamine ortri-(2-hydroxy-ethyl)-amine, or heterocyclic bases, for exampleN-ethyl-piperidine or N,N′-dimethylpiperazine. Mixtures of salts arepossible.

Compounds having both acidic and basic groups can form internal salts.

For the purposes of isolation or purification, as well as in the case ofcompounds that are used further as intermediates, it is also possible touse pharmaceutically unacceptable salts, e.g. the picrates. Onlypharmaceutically acceptable, non-toxic salts may be used forthera-peutic purposes, however, and those salts are therefore preferred.

Such salts are formed, for example, as acid addition salts, preferablywith organic or inorganic acids, from compounds of Formula (I) (or anexemplary formula thereof) with a basic nitrogen atom, especially thepharmaceutically acceptable salts. Suitable inorganic acids are, forexample, halogen acids, such as hydrochloric acid, sulfuric acid, orphosphoric acid. Suitable organic acids are, for example, carboxylic,phosphonic, sulfonic or sulfamic acids, for example acetic acid,propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolicacid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelicacid, suberic acid, azelaic acid, malic acid, tartaric acid, citricacid, amino acids, such as glutamic acid or aspartic acid, maleic acid,hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid,adamantanecarboxylic acid, benzoic acid, salicylic acid,4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid,cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonicacid, ethane-1,2-disulfonic acid, benzenesulfonic acid,2-naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid, 2-, 3- or4-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid,dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- orN-propyl-sulfamic acid, or other organic protonic acids, such asascorbic acid.

In the presence of negatively charged radicals, such as carboxy orsulfo, salts may also be formed with bases, e.g. metal or ammoniumsalts, such as alkali metal or alkaline earth metal salts, for examplesodium, potassium, magnesium or calcium salts, or ammonium salts withammonia or suitable organic amines, such as tertiary monoamines, forexample triethylamine or tri(2-hydroxyethyl)amine, or heterocyclicbases, for example N-ethyl-piperidine or N,N′-dimethylpiperazine.

When a basic group and an acid group are present in the same molecule, acompound of Formula (I) (or an exemplary formula thereof) may also forminternal salts.

For isolation or purification purposes it is also possible to usepharmaceutically unacceptable salts, for example picrates orperchlorates. For therapeutic use, only pharmaceutically acceptablesalts or free compounds are employed (where applicable in the form ofpharmaceutical preparations), and these are therefore preferred.

In view of the close relationship between the novel compounds in freeform and those in the form of their salts, including those salts thatcan be used as intermediates, for example in the purification oridentification of the novel compounds, any reference to the freecompounds hereinbefore and hereinafter is to be understood as referringalso to the corresponding salts, as appropriate and expedient.

The compounds of Formula (I) (or exemplary formulae thereof) andN-oxides thereof have valuable pharmacological properties, as describedhereinbefore and hereinafter.

Biology

The efficacy of the compounds of the invention as inhibitors of Bcr-Abl,EGF-R, VEGF-R2 (KDR) and FGFR3 (KDR) receptor tyrosine kinase activitycan be demonstrated as follows:

Test for Activity Against Bcr-Abl:

The murine myeloid progenitor cell line 32Dcl3 transfected with the p210Bcr-Abl expression vector pGDp210Bcr/Abl (32D-bcr/abl) was obtained fromJ. Griffin (Dana Faber Cancer Institue, Bosten, Mass., USA). The cellsexpress the fusion Bcr-Abl protein with a constitutively active ablkinase and proliferate growth factor independent. The cells are expandedin RPMI 1640 (AMIMED), 10% fetal calf serum, 2 mM glutamine (Gibco)(“complete medium”), and a working stock is prepared by freezingaliquots of 2×10⁶ cells per vial in freezing medium (95% FCS, 5% DMSO(SIGMA)). After thawing, the cells are used during maximally 10-12passages for the experiments. The antibody anti-abl SH3 domain cat.#06-466 from Upstate Biotechnology is used for the ELISA. For detectionof bcr-abl phosphorylation, the anti-phosphotyrosine antibody Ab PY20,labelled with alkaline phosphatase (PY10(AP)) from ZYMED (cat. #03-7722)is used. As comparison and reference compound,(N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine,in the form of the methane sulfonate (monomesylate) salt (STI571)(marketed as Gleevec® or Glivec®, Novartis), is used. A stock solutionof 10 mM is prepared in DMSO and stored at −20° C. For the cellularassays, the stock solution is diluted in complete medium in two steps(1:100 and 1:10) to yield a starting concentration of 10 μM followed bypreparation of serial threefold dilutions in complete medium. Nosolubility problems are encountered using this procedure. The testcompounds are treated analogously. For the assay, 200′000 32D-bcr/ablcells in 50 μl are seeded per well in 96 well round bottom tissueculture plates. 50 μl per well of serial threefold dilutions of the testcompound are added to the cells in triplicates. The final concentrationof the test compound range e.g. from 5 μM down to 0.01 μM. Untreatedcells are used as control. The compound is incubated together with thecells for 90 min at 37° C., 5% CO₂, followed by centrifugation of thetissue culture plates at 1300 rpm (Beckman GPR centrifuge) and removalof the supernatants by careful aspiration taking care not to remove anyof the pelleted cells. The cell pellets are lysed by addition of 150 μllysis buffer (50 mM Tris/HCl, pH 7.4, 150 mM sodium chloride, 5 mM EDTA,1 mM EGTA, 1% NP-40 (non-ionic detergent, Roche Diagnostics GmbH,Mannheim, Germany), 2 mM sodium ortho-vanadate, 1 mM phenylmethylsulfonylfluoride, 50 μg/ml aprotinin and 80 μg/ml leupeptin) and eitherused immediately for the ELISA or stored frozen at −20° C. until usage.The anti-abl SH3 domain antibody is coated at 200 ng in 50 μl PBS perwell to black ELISA plates (Packard HTRF-96 black plates; 6005207)overnight at 4° C. After washing 3× with 200 μl/well PBS containing0.05% Tween 20 (PBST) and 0.5% TopBlock (Juro, Cat. #TB 232010),residual protein binding sites are blocked with 200 μl/well PBST, 3%TopBlock for 4 h at room temperature, followed by incubation with 50 μllysates of untreated or test compound-treated cells (20 μg total proteinper well) for 3-4 h at 4° C. After 3× washing, 50 μl/well PY20(AP)(Zymed) diluted to 0.5 μg/ml in blocking buffer is added and incubatedovernight (4!C). For all incubation steps, the plates are covered withplate sealers (Costar, cat. #3095). Finally, the plates are washedanother three times with washing buffer and once with deionized waterbefore addition of 90 μl/well of the AP substrate CPDStar RTU withEmerald II. The plates now sealed with Packard Top Seal™-A plate sealers(cat. #6005185) are incubated for 45 min at room temperature in the darkand luminescence is quantified by measuring counts per second (CPS) witha Packard Top Count Microplate Scintillation Counter (Top Count). Forthe final optimized version of the ELISA, 50 μl of the lysates of thecells grown, treated and lysed in 96 well tissue culture plates, aretransferred directly from these plates to the ELISA plates that areprecoated with 50 ng/well of the rabbit poylclonal ant-abl-SH3 domain AB06-466 from Upstate. The concentration of the anti-phosphotyrosine ABPY20 (AP) can be reduced to 0.2 μg/ml. Washing, blocking and incubationwith the luminescent substrate are as above. The quantification isachieved as follows: The difference between the ELISA readout (CPS)obtained for with the lysates of the untreated 32D-bcr/abl cells and thereadout for the assay background (all components, but without celllysate) is calculated and taken as 100% reflecting the constitutivelyphosphorylated bcr-abl protein present in these cells. The activity ofthe compound in the bcr-abl kinase activity is expressed as percentreduction of the bcr-abl phosphorylation. The values for the IC₅₀ aredetermined from the dose response curves by graphical inter- orextrapolation. The compounds of the invention here preferably show IC₅₀values in the range from 15 nM to 500 μM, most preferably 15 nM to 200μM.

For cellular assays, compounds are dissolved in DMSO and diluted withcomplete medium to yield a starting concentration of 10 μM followed bypreparation of serial 3-fold dilutions in complete medium. 32D or Ba/F3cells expressing either ‘wt’-Bcr-Abl or Bcr-Abl mutants (e.g. T-315-I)were seeded at 200′000 cells in 50 μL complete medium are seeded perwell in 96 well round bottom tissue culture plates. 50 μL per well ofserial 3-fold dilutions of the test compound are added to the cells intriplicates. Untreated cells are used as control. The compound isincubated together with the cells for 90 min at 37° C., 5% CO₂, followedby centrifugation of the tissue culture plates at 1300 rpm (Beckmann GPRcentrifuge) and removal of the supernatants by careful aspiration takingcare not to remove any of the pelleted cells. The cell pellets are lysedby addition of 150 μL lysis buffer (50 mM Tris/HCl, pH 7.4, 150 mMsodium chloride, 5 mM EDTA, 1 mM EGTA, 1% NP-40, 2 mM sodiumortho-vanadate, 1 mM PMSF, 50 μg/mL aprotinin and 80 μg/mL leupeptin)and either used immediately for the ELISA or stored frozen in the platesat −20° C. until usage.

The rabbit polyclonal anti-abl-SH3 domain Ab 06-466 from Upstate wascoated at 50 ng in 50 μl PBS per well to black ELISA plates (PackardHTRF-96 black plates; 6005207) over night at 4° C. After washing 3 timeswith 200 μL/well PBS containing 0.05% Tween20 (PBST) and 0.5% TopBlock(Juro), residual protein binding sites are blocked with 200 μL/wellPBST, 3% TopBlock for 4 h at room temperature followed by incubationwith 50 L lysates of untreated or compound-treated cells (20 μg totalprotein per well) for 3-4 h at 4° C. After 3 washings, 50 μL/wellanti-phosphotyrosine Ab PY20(AP) labeled with alkaline phosphatase(Zymed) diluted to 0.2 μg/mL in blocking buffer is added and incubatedover night (4° C.). For all incubation steps the plates are covered withplate sealers (Costar). Finally, the plates are washed another threetimes with washing buffer and once with deionized water before additionof 90 μL/well of the AP-substrate CDPStar RTU with Emerald II. Theplates, now sealed with Packard TopSeal™-A plate sealers, are incubatedfor 45 min at room temperature in the dark and luminescence isquantified by measuring counts per second (CPS) with a Packard Top CountMicroplate Scintillation Counter (Top Count).

The difference between the ELISA-readout (CPS) obtained for with thelysates of the untreated 32D-Bcr/Abl cells and the readout for theassay-background (all components, but without cell lysate) is calculatedand taken as 100% reflecting the constitutively phosphorylated Bcr-Ablprotein present in these cells. The activity of the compound on theBcr-Abl kinase activity is expressed as percent reduction of the Bcr-Ablphosphorylation. The values for the IC₅₀ (and IC₉₀) are determined fromthe dose response curves by graphical extrapolation.

The compounds of the invention here preferably show IC₅₀ values below500 nM for inhibition of autophosphorylation and inhibition of IL-3independent proliferation of Bcr-Abl mutants in Ba/F3 transfected cells,in particular T315I.

The 32D cl3 cells were obtained from the American Type CultureCollection (ATCC CRL11346) and the Ba/F3 cells from the GermanCollection of Microorganisms and Cell Cultures (DSMZ, Braunschweig andDSMZ No. ACC 300)

-   Palacios et al., Nature, 309: 1984, 126, PubMed ID 6201749.-   Palacios et al., Cell, 41: 1985, 727, PubMed ID 3924409

The Ba/F3.p210 cells and the murine hematopoietic 32D cl3cells, (32Dp210 cells) were obtained by transfecting the IL-3-dependent murinehematopoietic Ba/F3 cell line with a pGD vector containing p210BCR-ABL(B2A2) cDNA

-   Daley and Baltimore, 1988; Sattler et al., 1996; Okuda et al., 1996.-   Daley, G. Q., Baltimore, D. (1988) Transformation of an interleukin    3-dependent hematopoietic cell line by the chronic myeloid    leukemia-specific p210 BCR-ABL protein. PNAS 85, 9312-9316-   Sattler M, Salgia R, Okuda K, Uemura N, Durstin M A, Pisick E, et    al. (1996) The proto-oncogene product p120CBL and the adaptor    proteins CRKL and c-CRK link c-ABL, p190BCR-ABL and p210BCR-ABL to    the phosphatidylinositol-3′ kinase pathway. Oncogene 12, 839-46.-   Okuda K, Golub T R, Gilliland D G, Griffin J D. (1996) p210BCR-ABL,    p190BCR-ABL, and TEL/ABL activate similar signal transduction    pathways in hematopoietic cell lines. Oncogene 13, 1147-52.    Test for Activity Against c-KIT

The baculovirus donor vector pFbacG01 GIBCO is used to generate arecombinant baculovirus that expresses the amino acid region amino acids544-976 of the cytoplasmic kinase domains of human c-Kit. The codingsequences for the cytoplasmic domain of c-Kit is amplified by PCR from ahuman uterus c-DNA library (Clontech). The amplified DNA fragment andthe pFbacG01 vector are made compatible for ligation by digestion withBamH1 and EcoRI. Ligation of these DNA fragments results in thebaculovirus donor plasmid c-Kit. The production of the viruses, theexpression of proteins in Sf9 cells and the purification of theGST-fused proteins are performed as follows:

Production of Virus:

Transfer vector pFbacG01-c-Kit containing the c-Kit kinase domain istransfected into the DH10Bac cell line (GIBCO) and the transfected cellsare plated on selective agar plates. Colonies without insertion of thefusion sequence into the viral genome (carried by the bacteria) areblue. Single white colonies are picked and viral DNA (bacmid) isisolated from the bacteria by standard plasmid purification procedures.Sf9 cells or Sf21 cells American Type Culture Collection are thentransfected in 25 cm² flasks with the viral DNA using Cellfectinreagent.

Determination of Small Scale Protein Expression in Sf9 Cells:

Virus containing media is collected from the transfected cell cultureand used for infection to increase its titer. Virus containing mediaobtained after two rounds of infection is used for large-scale proteinexpression. For large-scale protein expression 100 cm² round tissueculture plates are seeded with 5×10⁷ cells/plate and infected with 1 mLof virus-containing media (approx. 5 MOls). After 3 days the cells arescraped off the plate and centrifuged at 500 rpm for 5 min. Cell pelletsfrom 10-20, 100 cm² plates, are resuspended in 50 mL of ice-cold lysisbuffer (25 mM Tris-HCl, pH 7.5, 2 mM EDTA, 1% NP-40, 1 mM DTT, 1 mMPMSF). The cells are stirred on ice for 15 min and then centrifuged at5000 rpms for 20 min.

Purification of GST-tagged Protein:

The centrifuged cell lysate is loaded onto a 2 mL glutathione-sepharosecolumn (Pharmacia) and washed three times with 10 mL of 25 mM Tris-HCl,pH 7.5, 2 mM EDTA, 1 mM DTT, 200 mM NaCl. The GST-tagged protein iseluted by 10 applications (1 mL each) of 25 mM Tris-HCl, pH 7.5, 10 mMreduced-glutathione, 100 mM NaCl, 1 mM DTT, 10% Glycerol and stored at−70° C.

Kinase Assay:

Tyrosine protein kinase assays with purified GST-c-Kit are carried outin a final volume of 30 μL containing 200-1800 ng of enzyme protein(depending on the specific activity), 20 mM Tris-HCl, pH 7.6, 3 mMMnCl₂, 3 mM MgCl₂, 1 mM DTT, 10 μM Na₃VO₄, 5 μg/mL poly(Glu,Tyr) 4:1, 1%DMSO, 1.0 μM ATP and 0.1 μCi [γ³³P] ATP. The activity is assayed in thepresence or absence of inhibitors, by measuring the incorporation of ³³Pfrom [γ³³P] ATP into the poly(Glu,Tyr) 4:1 substrate. The assay (30 μL)is carried out in 96-well plates at ambient temperature for 20 min underconditions described below and terminated by the addition of 20 μL of125 mM EDTA. Subsequently, 40 μL of the reaction mixture is transferredonto Immobilon-PVDF membrane (Millipore, Bedford, Mass., USA) previouslysoaked for 5 min with methanol, rinsed with water, then soaked for 5 minwith 0.5% H₃PO₄ and mounted on vacuum manifold with disconnected vacuumsource. After spotting all samples, vacuum is connected and each wellrinsed with 200 μL 0.5% H₃PO₄. Membranes are removed and washed 4× on ashaker with 1.0% H₃PO₄ and once with ethanol. Membranes are countedafter drying at ambient temperature, mounting in Packard TopCount96-well frame, and addition of 10 μL/well of Microscint™ (Packard). IC₅₀values are calculated by linear regression analysis of the percentageinhibition of each compound in duplicate, at four concentrations(usually 0.01, 0.1, 1 and 10 μM). One unit of protein kinase activity isdefined as 1 nmole of ³³P ATP transferred from [γ³³P] ATP to thesubstrate protein per minute per mg of protein at 37° C.

Test for Activity Against EphB4

The efficacy of compounds of the formula I as inhibitors or Ephrin B4receptor (EphB4) kinases can be demonstrated as follows:

Generation of Bac-to-Bac™ (Invitrogen Life Technologies, Basel,Switzerland) GST-fusion expression vectors: Entire cytoplasmatic codingregions of the EphB-class are amplified by PCR from cDNA librariesderived from human placenta or brain, respectively. Recombinantbaculovirus are generated that express the amino acid region 566-987 ofthe human EphB4 receptor (SwissProt Database, Accession No. P54760). GSTsequence is cloned into pFastBac1® vector (Invitrogen Life Technologies,Basel, Switzerland) and PCR amplified. cDNAs encoding EphB4-receptordomains, respectively are cloned in frame 3′ prime to the GST sequenceinto this modified FastBac1 vector to generate pBac-to-Bac™ donorvectors. Single colonies arising from the transformation are inoculatedto give overnight cultures for small scale plasmid preparation.Restriction enzyme analysis of plasmid DNA reveals several clones tocontain inserts of the expected size. By automated sequencing theinserts and approximately 50 bp of the flanking vector sequences areconfirmed on both strands.

Production of viruses: Viruses for each of the kinases are madeaccording to the protocol supplied by GIBCO if not stated otherwise. Inbrief, transfer vectors containing the kinase domains are transfectedinto the DH10Bac cell line (GIBCO) and plated on selective agar plates.Colonies without insertion of the fusion sequence into the viral genome(carried by the bacteria) are blue. Single white colonies are picked andviral DNA (bacmid) isolated from the bacteria by standard plasmidpurification procedures. Sf9 cells or Sf21 cells are then transfected in25 cm² flasks with the viral DNA using Cellfectin reagent according tothe protocol.

Purification of GST-tagged kinases: The centrifuged cell lysate isloaded onto a 2 mL glutathione-sepharose column (Pharmacia) and washedthree times with 10 mL of 25 mM Tris-HCl, pH 7.5, 2 mM EDTA, 1 mM DTT,200 mM NaCl. The GST-tagged proteins are then eluted by 10 applications(1 mL each) of 25 mM Tris-HCl, pH 7.5, 10 mM reduced-glutathione, 100 mMNaCl, 1 mM DTT, 10% Glycerol and stored at −70° C.

Protein kinase assays: The activities of protein kinases are assayed inthe presence or absence of inhibitors, by measuring the incorporation of³³P from [γ³³P]ATP into a polymer of glutamic acid and tyrosine(poly(Glu,Tyr)) as a substrate. The kinase assays with purified GST-EphB(30 ng) are carried out for 15-30 min at ambient temperature in a finalvolume of 30 μL containing 20 mM Tris.HCl , pH 7.5, 10 mM MgCl₂, 3-50 mMMnCl₂, 0.01 mM Na₃VO₄, 1% DMSO, 1 mM DTT, 3 μg/mL poly(Glu,Tyr) 4:1(Sigma; St. Louis, Mo., USA) and 2.0-3.0 μM ATP (γ-[³³P]-ATP 0.1 μCi).The assay is terminated by the addition of 20 μL of 125 mM EDTA.Subsequently, 40 μl of the reaction mixture are transferred ontoImmobilon-PVDF membrane (Millipore, Bedford, Mass., USA) previouslysoaked for 5 min with methanol, rinsed with water, then soaked for 5 minwith 0.5% H₃PO₄ and mounted on vacuum manifold with disconnected vacuumsource. After spot-ting all samples, vacuum is connected and each wellrinsed with 200 μl 0.5% H₃PO₄. Membra-nes are removed and washed 4× on ashaker with 1.0% H₃PO₄, once with ethanol. Membranes are counted afterdrying at ambient temperature, mounting in Packard TopCount96-wellframe, and addition of 10 μL/well of Microscint™ (Packard). IC₅₀ valuesare calculated by linear regression analysis of the percentageinhibition of each compound in duplicate, at four concentrations(usually 0.01, 0.1, 1 and 10 μM). One unit of protein kinase activity isdefined as 1 nmole of ³³P ATP transferred from [γ³³P] ATP to thesubstrate protein per minute per mg of protein at 37° C.

Test for Activity Against EGF-R:

The inhibition of EGF-R tyrosine kinase activity can be demonstratedusing known methods, for example using the recombinant intracellulardomain of the EGF-receptor [EGF-R ICD; see, for example, E. McGlynn etal., Europ. J. Biochem. 207, 265-275 (1992)]. Compared with the controlwithout inhibitor, the compounds of formula I inhibit the enzymeactivity by 50% (IC₅₀), for example in a concentration of from 0.0005 to0.5 μM, especially from 0.001 to 0.1 μM.

As well as or instead of inhibiting EGF-R tyrosine kinase activity, thecompounds of formula I also inhibit other members of this family ofreceptors, like ErbB-2. The inhibitory activity (IC₅₀) is approximatelyin the range of 0.001 to 0.5 μM. The inhibition of ErbB-2 tyrosinekinase (HER-2) can be determined, for example, analogously to the methodused for EGF-R protein tyrosine kinase [see C. House et al., Europ. J.Biochem. 140, 363-367 (1984)]. The ErbB-2 kinase can be isolated, andits activity determined, by means of protocols known per se, for examplein accordance with T. Akiyama et al., Science 232, 1644 (1986).

Test for Activity Against VEGF-R2 (KDR):

The inhibition of VEGF-induced receptor autophosphorylation can beconfirmed with a further in vitro experiments in cells such astransfected CHO cells, which permanently express hu-man VEGF-R2 receptor(KDR), are seeded in complete culture medium (with 10% fetal calfserum=FCS) in 6-well cell-culture plates and incubated at 37° C. under5% CO₂ until they show about 80% confluency. The compounds to be testedare then diluted in culture medium (without FCS, with 0.1% bovine serumalbumin) and added to the cells. (Controls comprise medium without testcompounds). After two hours of incubation at 37° C., recombinant VEGF isadded; the final VEGF concentration is 20 ng/ml. After a further fiveminutes incubation at 37° C., the cells are washed twice with ice-coldPBS (phosphate-buffered saline) and immediately lysed in 100 μl lysisbuffer per well. The lysates are then centrifuged to remove the cellnuclei, and the protein concentrations of the supernatants aredetermined using a commercial protein assay (BIORAD). The lysates canthen either be immediately used or, if necessary, stored at −20° C.

A sandwich ELISA is carried out to measure the VEGF-R2 phosphorylation:a monoclonal antibody to VEGF-R2 (for example Mab 1495.12.14; preparedby H. Towbin, Novartis or comparable monoclonal antibody) is immobilizedon black ELISA plates (OptiPlate™ HTRF-96 from Packard). The plates arethen washed and the remaining free protein-binding sites are saturatedwith 3% TopBlock® (Juro, Cat. #TB232010) in phosphate buffered salinewith Tween 20® (polyoxyethylen(20)sorbitane monolaurate, ICl/Uniquema)(PBST). The cell lysates (20 μg protein per well) are then incubated inthese plates overnight at 4° C. together with an antiphosphotyrosineantibody coupled with alkaline phosphatase (PY20:AP from Zymed). The(plates are washed again and the) binding of the antiphosphotyrosineantibody to the captured phosphorylated receptor is then demonstratedusing a luminescent AP sub-strate (CDP-Star, ready to use, with EmeraldII; Applied Biosystems). The luminescence is measured in a Packard TopCount Microplate Scintillation Counter. The difference between thesignal of the positive control (stimulated with VEGF) and that of thenegative control (not stimulated with VEGF) corresponds to VEGF-inducedVEGF-R2 phosphorylation (=100%). The activity of the tested substancesis calculated as percent inhibition of VEGF-induced VEGF-R2phosphorylation, wherein the concentration of substance that induceshalf the maximum inhibition is defined as the IC₅₀ (inhibitory dose for50% inhibition).

Test for Activity Against Recombinant Protein Kinases Ret (Ret-Men2A),Tie-2 (Tek) and FGFR3-K650E: Cloning and Expression of RecombinantProtein Kinases:

(Ret); The Baculovirus donor vector pFB-GSTX3 was used to generate arecombinant Baculovirus that expresses the amino acid region 658-1072 ofthe intra-cytoplasmic kinase domain of human Ret-Men2A which correspondsto the wild type kinase domain of Ret. The coding sequence for thecytoplasmic domain of Ret was amplified by PCR from the plasmidpBABEpuro RET-Men2A which was received from Dr. James Fagin, College ofMedicine, University of Cincinnati (Novartis collaboration). Theamplified DNA fragments and the pFB-GSTX3 vector were made compatiblefor ligation by digestion with SalI and KpnI. Ligation of these DNAfragments resulted in the baculovirus donor plasmid pFB-GX3-Ret(-Men2A).

(Tie-2/Tek): The baculovirus donor vector pFbacG01 was used to generatea recombinant baculovirus that expressed the amino acid region aminoacids 773-1124 of the cytoplasmic kinase domain of human Tek,N-terminally fused to GST (Provided by Dr. Marmé, Institute of MolecularMedicine, Freiburg, Germany based on a Research Collaboration). Tek wasrecloned into the pFbacG01 transfer vector by EcoRI excision andligation into EcoRI digested pFbacG01 (FBG-Tie2/Tek).

(FGFR-3-K650E): The baculovirus donor vector pFastBacGST2 was used togenerate a recombinant baculovirus that expressed the amino acid (aa)region amino acids 411-806 of the cytoplasmic domain of human FGFR-3,N-terminally fused to GST (Provided by Dr. Jim Griffin, Dana FarberCancer Institute, Boston, USA based on a Research Collaboration). DNAencoding amino acids 411-806 was amplified by PCR, inserted into thepFastBac-GT2 vector to yield pFB-GT2-FGFR3-wt. This plasmid was in turnused to generate a vector encoding FGFR3(411-806) with a mutation atK650 using the Stratagene XL-Site directed Mutagenesis Kit to producepFB-GT2-FGFR3-K650E. The production of the viruses, the expression ofproteins in Sf9 cells and the purification of the GST-fused proteinswere performed as described in the following sections.

Production of Virus:

Transfer vectors containing the kinase domains were transfected into theDH10Bac cell line (GIBCO) and plated on selective agar plates. Colonieswithout insertion of the fusion sequence into the viral genome (carriedby the bacteria) are blue. Single white colonies were picked and viralDNA (bacmid) isolated from the bacteria by standard plasmid purificationprocedures. Sf9 cells or Sf21 cells were then transfected in 25 cm²flasks with the viral DNA using Cellfectin reagent.

Determination of Small Scale Protein Expression in Sf9 Cells:

Virus containing media was collected from the transfected cell cultureand used for infection to increase its titer. Virus containing mediaobtained after two rounds of infection was used for large-scale proteinexpression. For large-scale protein expression 100 cm² round tissueculture plates were seeded with 5×10⁷ cells/plate and infected with 1 mLof virus-containing media (approx. 5 MOls). After 3 days the cells werescraped off the plate and centrifuged at 500 rpm for 5 min. Cell pelletsfrom 10-20, 100 cm² plates, were resuspended in 50 mL of ice-cold lysisbuffer (25 mMTris-HCl, pH7.5, 2 mMEDTA, 1% NP-40, 1 mM DTT, 1 mMPMSF).The cells were stirred on ice for 15 min and then centrifuged at5000 rpms for 20 min.

Purification of GST-tagged Proteins:

The centrifuged cell lysate was loaded onto a 2 mL glutathione-sepharosecolumn and washed three times with 10 mL of 25 mM Tris-HCl, pH 7.5, 2 mMEDTA, 1 mM DTT, 200 mM NaCl. The GST-tagged proteins were then eluted by10 applications (1 mL each) of 25 mM Tris-HCl, pH 7.5, 10 mMreduced-glutathione, 100 mM NaCl, 1 mM DTT, 10% Glycerol and stored at−70° C.

Measure of Enzyme Activity:

Tyrosine protein kinase assays with either purified GST-Ret, GST-Tek orGST-FGFR-3-K650E were carried out in a final volume of 30 μL with finalconcentrations of the following components: Ret included 15 ng ofGST-Ret , 20 mM Tris-HCl, pH 7.5, 1 mM MnCl₂, 10 mM MgCl₂, 1 mM DTT, 3μg/mL poly(Glu,Tyr) 4:1, 1% DMSO and 2.0 μM ATP (γ-[³³P]-ATP 0.1 μCi).Tek included 150 ng of GST-Tek , 20 mM Tris-HCl, pH 7.5, 3 mM MnCl₂, 3mM MgCl₂, 1 mM DTT, 0.01 mM Na₃VO₄, 250 μg/mL PEG 20′000, 10 μg/mLpoly(Glu,Tyr) 4:1, 1% DMSO and 4.0 μM ATP (γ-[³³P]-ATP 0.1 μCi).FGFR-3-K650E included 10 ng of GST- FGFR-3-K650E , 20 mM Tris-HCl, pH7.5, 3 mM MnCl₂, 3 mM MgCl₂, 1 mM DTT, 0.01 mM PEG 20′000, 10 μg/mLpoly(Glu,Tyr) 4:1, 1% DMSO and 4.0 μM ATP (γ-[³³P]-ATP 0.1 μCi). Theactivity was assayed in the presence or absence of inhibitors, bymeasuring the incorporation of ³³P from [γ³³P] ATP into poly(Glu,Tyr)4:1. The assay was carried out in 96-well plates at ambient temperaturefor 30 min under conditions described below and terminated by theaddition of 50 μL of 125 mM EDTA. Subsequently, 60 μL of the reactionmixture were transferred onto Immobilon-PVDF membrane (Millipore)previously soaked for 5 min with methanol, rinsed with water, thensoaked for 5 min with 0.5% H₃PO₄ and mounted on vacuum manifold withdisconnected vacuum source. After spotting all samples, vacuum wasconnected and each well rinsed with 200 μL 0.5% H₃PO₄. Membranes wereremoved and washed 4× on a shaker with 1.0% H₃PO₄, once with ethanol.Membranes were counted after drying at ambient temperature, mounting inPackard TopCount 96-well frame, and addition of 10 μL/well ofMicroscint™ (Packard). IC50 values were calculated by linear regressionanalysis of the percentage inhibition of each compound in duplicate, atfour concentrations (usually 0.01, 0.1, 1 and 10 μM). One unit ofprotein kinase activity is defined as 1 nmole of ³³P ATP transferredfrom [γ³³P] ATP to the substrate protein per minute per mg of protein at37° C.

On the basis of the inhibitory studies hereinbefore described, acompound of Formula (I) or (I*) (or exemplary formula thereof) accordingto the invention shows therapeutic efficacy especially against disordersdependent on protein kinase, especially proliferative diseases.

The heteroaryl aryl ureas useful according to the invention, especiallycompounds of Formula (I) (or exemplary formula thereof), that inhibitthe protein kinase activities mentioned, especially tyrosine proteinkinases mentioned above and below, can therefore be used in thetreatment of protein kinase dependent diseases. Protein kinase dependentdiseases are especially proliferative diseases, preferably benign orespecially malignant tumours (for example carcinoma of the kidneys,liver, adrenal glands, bladder, breast, stomach, ovaries, colon, rectum,prostate, pancreas, lungs, vagina or thyroid, sarcoma, glioblastomas andnumerous tumours of the neck and head, as well as leukemias). They areable to bring about the regression of tumours and to prevent theformation of tumour metastases and the growth of (also micro)metastases.In addition they can be used in epidermal hyperproliferation (e.g.psoriasis), in prostate hyperplasia, and in the treatment of neoplasias,especially of epithelial character, for example mammary carcinoma. It isalso possible to use the compounds of Formula (I) (or exemplary formulathereof) in the treatment of diseases of the immune system insofar asseveral or, especially, individual tyrosine protein kinases areinvolved; furthermore, the compounds of Formula (I) (or exemplaryformula thereof) can be used also in the treatment of diseases of thecentral or peripheral nervous system where signal transmission by atleast one tyrosine protein kinase, especially selected from thosementioned specifically, is involved.

The expression of FGFR1 (also known as “Flg”), FGFR2 (also known as“Bek”) and the like belonging to a fibroblast growth factor receptorfamily is reported to be found in various cancers such as brain tumors,lung cancer, breast cancer, gastric cancer, head and neck cancer, andprostatic cancer (Proc. Natl. Acad. Sci. USA, 87: 5710-5714 (1990);Oncogene. 1997 Aug. 14; 15 (7): 817-26; Cancer Res. 1994 Jan. 15; 54(2): 523-30; Cancer Res. 1992 Feb. 1; 52 (3): 571-7). In particular, itis reported for gastric cancer that overexpression of FGFR2 correlateswith poor prognosis mainly in poorly differentiated cancers such asscirrhus gastric cancers (Clin Cancer Res. 1996 August; 2 (8): 1373-81;J Cancer Res Clin Oncol. 2001 April; 127 (4): 207-16; Int Rev Cytol.2001; 204: 49-95.). Further diseases associated with FGFR1 and FGFR4 arediabetes and obesity.

Diseases related to FGFR1, FGFR2, FGFR3 and FGFR4 are describedpreviously herein under the heading “BACKGROUND”, and as inhibitors ofthese kinases the compounds of the invention may find application intreating those diseases.

As inhibitors of VEGF-receptor tyrosine kinase activity, the compoundsof the invention may primarily inhibit the growth of blood vessels andare thus, for example, effective against a number of diseases associatedwith deregulated angiogenesis, especially diseases caused by ocularneovascularisation, especially retinopathies, such as diabeticretinopathy or age-related macula degeneration, psoriasis,haemangioblastoma, such as haemangioma, mesangial cell proliferativedisorders, such as chronic or acute renal diseases, e.g. diabeticnephropathy, malignant nephrosclerosis, thrombotic microangiopathysyndromes or transplant rejection, or especially inflammatory renaldisease, such as glomerulonephritis, especially mesangioproliferativeglomerulonephritis, haemolytic-uraemic syndrome, diabetic nephropathy,hypertensive nephrosclerosis, atheroma, arterial restenosis, autoimmunediseases, diabetes, endometriosis, chronic asthma, and especiallyneoplastic diseases (solid tumors, but also leukemias and other “liquidtumors”, especially those expressing KDR), such as especially breastcancer, cancer of the colon, lung cancer (especially small-cell lungcancer), cancer of the prostate or Kaposi's sarcoma. A compound ofFormula (I) (or exemplary formula thereof) (or an N-oxide thereof)inhibits the growth of tumours and is especially suited to preventingthe metastatic spread of tumors and the growth of micrometastases.

Vascular endothelial growth factor receptor-2 (VEGF-R2; KDR) isselectively expressed on the primary vascular endothelium and isessential for normal vascular development. In order to grow beyondminimal size, tumors must generate new vascular supply. Angiogenesis, orthe sprouting of new blood vessels, is a central process in the growthof solid tumors. For many cancers, the extent of vascularization of atumor is a negative prognostic indicator signifying aggressive diseaseand increased potential for metastasis. Recent efforts to un-derstandthe molecular basis of tumor-associated angiogenesis have identifiedseveral po-tential therapeutic targets, including the receptor tyrosinekinases for the angiogenic factor vascular endothelial growth factor(VEGF) (see Zeng et al., J. Biol. Chem. 276(35), 32714-32719 (2001)).The heteroaryl aryl ureas according to the present invention, especiallythe compounds of Formula (I) (or exemplary formula thereof) for use asKDR inhibitors are thus especially appropriate for the therapy ofdiseases related to VEGF receptor tyrosine kinase overexpression. Amongthese diseases, especially retinopathies, age-related maculadegeneration, psoriasis, haemangioblastoma, haemangioma,arteriosclerosis, inflammatory diseases, such as rheumatoid or rheumaticinflammatory diseases, especially arthritis, such as rheumatoidarthritis, or other chronic inflammatory disorders, such as chronicasthma, arterial or post-transplantational atherosclerosis,endometriosis, and especially neoplastic diseases, for example so-calledsolid tumors (especially cancers of the gastrointestinal tract, thepancreas, breast, stomach, cervix, bladder, kidney, prostate, ovaries,endometrium, lung, brain, melanoma, Kaposi's sarcoma, squamous cellcarcinoma of heand and neck, malignant pleural mesotherioma, lymphoma ormultiple myeloma) and liquid tumors (e.g. leukemias) are especiallyimportant.

In particular, the present invention pertains to the use of a compoundof Formula I for the manufacture of a medicament for the treatment of aproliferative disorder, a skeletal disorder, a cancer, a solid tumour,especially an epithelial cancer, a T cell mediated inflammatory orautoimmune disease.

In chronic myelogeous leukemia (CML), a reciprocally balancedchromosomal translocation in hematopoietic stem cells (HSCs) producesthe BCR-ABL hybrid gene. The latter encodes the oncogenic Bcr-Abl fusionprotein. Whereas ABL encodes a tightly regulated protein tyro-sinekinase, which plays a fundamental role in regulating cell proliferation,adherence and apoptosis, the BCR-ABL fusion gene encodes asconstitutively activated kinase, which trans-forms HSCs to produce aphenotype exhibiting deregulated clonal proliferation, reduced capacityto adhere to the bone marrow stroma and a reduces apoptotic response tomutagenic stimuli, which enable it to accumulate progressively moremalignant transformations. The re-sulting granulocytes fail to developinto mature lymphocytes and are released into the circu-lation, leadingto a deficiency in the mature cells and increased susceptibility toinfection. ATP-competitive inhibitors of Bcr-Abl have been describedwhich prevent the kinase from activating mitogenic and anti-apoptoticpathways (e.g. P-3 kinase and STAT5), leading to the death of theBCR-ABL phenotype cells and thereby providing an effective therapyagainst CML. The heteroaryl aryl ureas useful according to the presentinvention, especially the compounds of the Formula (I) (or exemplaryformula thereof) are thus especially appropriate for the therapy ofdiseases related to its overexpression, especially leukemias, such asleukemias, e.g. CML or ALL.

Compounds of the Formula I*, II*, III*, IV*, V*, VI*, VII*, VIII* or IX*(or exemplary formula thereof), in view of their activity as PDGFreceptor inhibitors, are also especially appropriate in the treatment ofproliferate diseases, especially small lung cancer, atherosclerosis,thrombosis, psoriasis, scleroderma or fibrosis.

There are also experiments to demonstrate the antitumor activity ofcompounds of the Formula (I) (or exemplary formula thereof) in vivo: Thein vivo antitumor activity is tested, for example, using breastcarcinoma cell lines, such as the human estrogen dependent breastcarcinoma MCF-7 (ATCC: HTB22) or ZR-75-1 (ATCC: CRL1500), or theestrogen-independent breast carcinomas MDA-MB468 (ATCC: HTB132) orMDA-MB231 (ATCC: HTB26); colon carcinoma cell lines, such as thecolon-carcinoma Cob 205 (ATCC: CCL222); glioblastoma cell lines, such asthe glioblastomas U-87MG (ATCC: HTB14) or U-373MG (ATCC: HTB17); lungcarcinoma cell lines, such as the “small cell lung carcinomas” NCI-H69(ATCC: HTB119) or NCI-H209 (ATCC: HTB172), or the lung carcinomaNCI-H596 (ATCC: HTB178); skin tumor cell lines, such as the melanomasHs294T (ATCC: HTB140) or A375 (ATCC: CRL1619); tumor cell lines from thegenitourinry systems, such as the ovarial carcinoma NIH-Ovcar3 (ATCC:HTB161), as well as the prostate carzinomas DU145 (ATCC: HTB81) or PC-3(ATCC: CRL1435), or the bladder carcinoma T24 (ATCC: HTB4); epithelialcarcinomas, such as the epithelial carcinoma KB31; or (especially withregard to leukemias) K562 cells (American Type Culture Collection,Mannassas, Va.) or human CFU-G cells (CFU-G stands for granulocytecolony forming unit, and it represents an early but committedgranulocyte forming precursor cell that circulates in the blood streamor bone marrow) each of which is transplanted into female or male Balb/cnude mice. Other cell lines include leukemic cell lines such as K-562,SUPB15, MEG01, Ku812F, MOLM-13, BaF3, CEM/0, JURKAT/0 or U87MG.

Tumors are obtained after subcutaneous injection of the respective cells(minimum 2×10⁶ cells in 100 ml phosphate buffered physiological saline)into the carrier mice (e.g. 4-8 mice per cell line). The resultingtumors are passed serially through at least three subsequenttransplantations before treatment is started. Tumor fragments (about 25mg each) are in-jected s.c. into the left flank of the animals using a13-gauge Trocar needle under Forene narcosis (Abbott, Switzerland) forimplantation. Mice transplanted with estrogen-dependent tumor are, inaddition, supplied with an estrogen pellet (1.0 cm of a tube with aquality appropriate for medical purposes, Dow Chemicals, with 5 mgestradiole, Sigma). The treat-ment is started routinely (that is at lowor intermediate tumor burden), as soon as the tumor has reached anaverage size of 100 mm³. Tumor growth is determined once, twice orthrice weekly (depending on tumor growth of the cell line) and 24 hafter the last treatment by measurement of the perpendicular diameter.In case of tumors, tumor volumes are deter-mined according to theFormula L×D×p/6 (see Evans, B. D., Smith, I. E., Shorthouse, A. J. andMillar, J. J., Brit. J. Cancer, 45: 466-468, 1982). The antitumoractivity is expressed as T/C % (average increase of the tumor volume oftreated animals divided by the average increase of tumor volume incontrol animals multiplied by 100). Tumor regression (%) re-presents thesmallest mean tumor volume compared to the mean tumor volume at thebeginning of the treatment. Each animal in which the tumor reaches adiameter of more than 1,5 to 2 cm³ is sacrificed. Leukemia burden isassessed by examining both peripheral white blood count and weight ofspleen and thymus in animals tumored with leukemia cell lines.

An exemplary (though not limiting) schedule for administration of aheteroaryl aryl urea, es-pecially of Formula (I) (or exemplary formulathereof), or a salt thereof, is daily ad-ministration, with preferably 1to 3 daily dosages for a longer time, possibly until the disease iscured or, if only palliateive treatment is achieved, for as long asrequired; alternatively, treatment e.g. for 5 days, and/oradministration at days 1, 4 and 9, with eventual repetition after acertain time without treatment is possible. Alternatively, treatmentseveral times a day (e.g. 2 to 5 times) or treatment by continuousadministration (e.g. infusion), e.g. at the time points indicated in thelast sentence, are possible. Generally, administration is orally orparenterally, preferably orally. The test compounds are preferablydiluted in water or in sterile 0.9% saline.

All human tumor cell lines are obtained from the American Type CultureCollection (ATCC, Rockville, Md., USA) if not indicated otherwise andare cultivated in the suggested media with the corresponding additives(ATCC culture conditions), if not mentioned otherwise. The c-sis- andv-sis-transformed BALB/c 3T3 cells are obtained from Dr. C. Stiles (DanaFarber Cancer Institute, Boston, Mass., USA). They are cultured in“Dulbecco's modified Eagle's me-dium” (DMEM), that is supplemented with10% calf serum and Hygromycin B in a concen-tration of 0.2 mg/ml or G418in a concentration of 0.5 mg/ml. BALB/c AMuLV A.6R.1 cells (ATCC) arekept in DMEM, supplemented with 10% fetal calf serum.

The pharmacological activity of a heteroaryl aryl urea of the Formula(I) (or exemplary formula thereof) may, for example, be demonstrated ina clinical study or in a test procedure as essentially describedhereinafter.

Suitable clinical studies are, for example, open label non-randomized,dose escalation stu-dies in patients with one of the tumor diseasesmentioned above. The beneficial effects on proliferative diseases can bedetermined directly through the results of these studies or by changesin the study design which are known as such to a person skilled in theart. The effi-cacy of the treatment can be determined in such studies,e.g., in case of tumors after 18 or 24 weeks by radiologic evaluation ofthe tumors every 6 weeks, in case of a leukemia e.g. by determination ofthe count of aberrant white blood cells, and by staining mononuclearcells and/or by means of determining minimum residual disease (MRD) e.g.by FACS-LPC MRD or PCR.

Alternatively, a placebo-controlled, double blind study can be used inorder to prove the bene-fits of the heteroaryl aryl ureas usefulaccording to the invention, especially the compounds of the Formula (I)(or exemplary formula thereof) mentioned herein.

In a further embodiment, the present invention provides compounds ofFormula I** representing a sub-group of the compounds of Formula I,

-   -   in which    -   is selected from 0, 1 and 2;    -   s is selected from 0 and 1;    -   X¹ is selected from O or S;    -   X is CR₆;    -   Y and Z are both nitrogen;    -   R₁ is selected from —X5NR₇R₈, —X5NR₇X5NR₇R₈, —X5NR₇X5C(O)OR₈,        —X5OR₇, —X5R₇ and —X5S(O)₀₋₂R₇; wherein X5 is a bond or        C₁₋₄alkylene optionally substituted by 1 to 2 C₁₋₆alkyl        radicals; R₇ is selected from hydrogen, C₁₋₆alkyl,        C₆₋₁₀aryl-C₀₋₄alkyl, C₅₋₁₀heteroaryl-C₀₋₄alkyl,        C₃₋₁₀cycloalkyl-C₀₋₄alkyl and C₃₋₁₀heterocycloalkyl-C₀₋₄alkyl;        and R₆ is selected from hydrogen and C₁₋₆alkyl; or R₇ and R₈        together with the nitrogen to which R₇ and R₈ are both attached        form heteroaryl or heterocycloalkyl;    -   wherein any aryl, heteroaryl, cycloalkyl and heterocycloalkyl of        R₇ or the combination of R₇ and R₈ can be optionally substituted        with 1 to 3 radicals independently selected from halo, nitro,        cyano, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-alkyl,        halo-substituted-alkoxy, —X5NR₉R₁₀, —X5OR₉, —X5NR₉S(O)₂R₁₀,        —X5NR₉S(O)R₁₀, —X5NR₉SR₁₀, —X5C(O)NR₉R₁₀, —X5NR₉C(O)NR₉R₁₀,        —X5NR₉C(O)R₁₀, —X5NR₉X5NR₉R₁₀, —X5NR₉X5OR₉, —X5NR₉C(═NR₉)NR₉R₁₀,        —X5S(O)₀₋₂R₁₁, —X5NR₉C(O)R₁₀, —X5NR₉C(O)R₁₁, —X5R₁₁,        —X5C(O)OR₁₀, —X5S(O)₂NR₉R₁₀, —X5S(O)NR₉R₁₀ and —X5SNR₉R₁₀;        wherein X5 is a bond or C₁₋₄alkylene; R₉ and R₁₀ are        independently selected from hydrogen and C₁₋₄alkyl; and R₁₁ is        C₃₋₁₀heterocycloalkyl optionally substituted with 1 to 3        radicals selected from C₁₋₄alkyl, —X5NR₉X5NR₉R₉, X5NR₉X5OR₉ and        —X5OR₉;    -   R₃ is selected from hydrogen, C₁₋₄alkyl, C₆₋₁₀aryl-C₀₋₄alkyl,        C₅₋₁₀heteroaryl-C₀₋₄-alkyl, C₃₋₁₀cycloalkyl-C₀₋₄alkyl and        C₃₋₁₀heterocycloalkyl-C₀₋₄alkyl; wherein any alkyl, aryl,        heteroaryl, cycloalkyl or heterocycloalkyl of R₃ is optionally        substituted by 1-3 radicals selected from halo, C₁₋₄alkyl,        —X5S(O)₀₋₂NR₉R₁₀ and —X5OR₉; wherein X5, R₉ and R₁₀ are as        described above;    -   R₄₅ is selected from C₆₋₁₀aryl-C₀₋₄alkyl,        C₅₋₁₀heteroaryl-C₀₋₄alkyl, C₃₋₁₀cycloalkyl-C₀₋₄alkyl and        C₃₋₁₀heterocycloalkyl-C₀₋₄alkyl; wherein any aryl, heteroaryl,        cycloalkyl or heterocycloalkyl of R₄₅ is optionally substituted        with 1 to 3 radicals selected from halo, hydroxy, C₁₋₄alkyl,        C₁₋₄alkoxy, halo-substituted-C₁₋₄alkyl,        halo-substituted-C₁₋₄alkoxy and C₃₋₈heterocycloC₀₋₄alkyl;        wherein any heterocycloalkyl substituent of R₄ is optionally        substituted by 1 to 3 C₁₋₄alkyl radicals;    -   R₂, R₆ and R₃₅ are independently selected from halo, hydroxy,        C₁₋₄alkyl, C₁₋₄alkoxy, halo-substituted-C₁₋₄alkyl and        halo-substituted-C₁₋₄alkoxy; and the N-oxide derivatives,        prodrug derivatives, protected derivatives, individual isomers        and mixture of isomers thereof; and the pharmaceutically        acceptable salts and solvates (e.g. hydrates) of such compounds.

For the definition of the compound of Formula I**, the followingdefinitions apply:

“Alkyl” as a group and as a structural element of other groups, forexample halo-substituted-alkyl and alkoxy, can be eitherstraight-chained or branched. C₁₋₄-alkoxy includes, methoxy, ethoxy, andthe like. Halo-substituted alkyl includes trifluoromethyl,pentafluoroethyl, and the like.

“Aryl” means a monocyclic or fused bicyclic aromatic ring assemblycontaining six to ten ring carbon atoms. For example, aryl may be phenylor naphthyl, preferably phenyl. “Arylene” means a divalent radicalderived from an aryl group.

“Heteroaryl” is as defined for aryl above where one or mom of the ringmembers is a heteroatom. For example heteroaryl includes pyridyl,indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl,benzopyranyl, benzothiopyranyl, benzo[1,3]dioxole, imidazolyl,benzo-imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl,tetrazolyl, pyrazolyl, thienyl, etc.

“Cycloalkyl” means a saturated or partially unsaturated, monocyclic,fused bicyclic or bridged polycyclic ring assembly containing the numberof ring atoms indicated. For example, C₃₋₁₀cycloalkyl includescyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

“Heterocycloalkyl” means cycloalkyl, as defined in this application,provided that one or more of the ring carbons indicated, are replaced bya moiety selected from —O—, —N═, —NR—, —C(O)—, —S—, —S(O)— or —S(O)₂—,wherein R is hydrogen, C₁₋₄alkyl or a nitrogen protecting group. Forexample, C₃₋₈heterocycloalkyl as used in this application to describecompounds of the invention includes morpholino, pyrrolidinyl,pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperidinylone,1,4-dioxa-8-aza-spiro[4.5]clec-8-yl, etc.

“Halogen” (or halo) preferably represents chloro or fluoro, but may alsobe bromo or iodo.

“Mutant forms of BCR-Abl” means single or multiple amino acid changesfrom the wild-type sequence. Over 22 mutations have been reported todate with the most common being G250E, E255V, T315I, F317L and M351T.

“Treat”, “treating” and “treatment” refer to a method of alleviating orabating a disease and/or its attendant symptoms.

The fusion protein BCR-Abl is a result of a reciprocal translocationthat fuses the Abl proto-oncogene with the Bcr gene. BCR-Abl is thencapable of transforming B-cells through the increase of mitogenicactivity. This increase results in a reduction of sensitivity toapoptosis, as well as altering the adhesion and homing of CML progenitorcells. The present invention provides compounds of Formula I**,compositions and methods for the treatment of kinase related disease,particularly Abl, BCR-Abl, BMX, FGFR35, Lck, JNK1, JNK2, CSK, RAF, MKK6and P38kinase related diseases. For example, leukemia and otherproliferation disorders related to BCR-Abl can be treated through theinhibition of wild type and mutant forms of BCR-Abl.

With reference to compounds of Formula I**, preferably

r is selected from 0, 1 and 2;s is selected from 0 and 1;X₁ is selected from O or S;R₁ is selected from —X5NR₇R₈, —X5NR₇X5NR₇R₈, —X5NR₇X5C(O)OR₈; wherein X5is a bond or C₁₋₄alkylene optionally substituted by 1 to 2 C₁₋₆alkylradicals; R₇ is selected from hydrogen, C₁₋₆alkyl, C₆₋₁₀aryl-C₀₋₄alkyl,C₅₋₁₀heteroaryl-C₀₋₄alkyl, C₃₋₁₀cycloalkyl-C₀₋₄alkyl andC₃₋₁₀heterocycloalkyl-C₀₋₄alkyl; and R₈ is selected from hydrogen andC₁₋₆alkyl; or R₇ and R₈ together with the nitrogen to which R₇ and R₈are both attached form heteroaryl or heterocycloalkyl;

-   -   wherein any aryl, heteroaryl, cycloalkyl and heterocycloalkyl of        R₇ or the combination of R₇ and R₈ can be optionally substituted        with 1 to 3 radicals independently selected from halo,        C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-alkyl, —X5NR₉R₁₀,        —X5C(O)NR₉R₁₀, —X5NR₉C(O)R₁₀, —X5S(O)₀₋₂R₁₁, —X5R₁₁; R₉ and R₁₀        are independently selected from hydrogen and C₁₋₄alkyl; and R₁₁        is C₃₋₁₀heterocycloalkyl optionally substituted with 1 to 3        C₁₋₄alkyl radicals;    -   R₃ is selected from hydrogen, C₁₋₄alkyl, C₆₋₁₀aryl-C₀₋₄alkyl,        C₅₋₁₀heteroaryl-C₀₋₄alkyl, C₃₋₁₀cycloalkyl-C₀₋₄alkyl and        C₃₋₁₀heterocycloalkyl-C₀₋₄alkyl; wherein any alkyl, aryl,        heteroaryl, cycloalkyl or heterocycloalkyl of R3 is optionally        substituted by 1-3 radicals selected from halo, C₁₋₄alkyl,        —X5S(O)₀₋₂NR₉R₁₀ and —X5OR₉; wherein X5, R₉ and R₁₀ are as        described above;    -   R₄₅ is selected from C₆₋₁₀aryl-C₀₋₄alkyl optionally substituted        with 1 to 3 radicals selected from halo-substituted-C₁₋₄alkyl        and C₃₋₈heterocycloC₀₋₄ alkyl; wherein any heterocycloalkyl        substituent of R45 is optionally substituted by 1 to 3 C₁₋₄alkyl        radicals;    -   R₃₅, R2 and R₆ are independently selected from halo, C₁₋₄alkyl,        C₁₋₄alkoxy, and halo-substituted-C₁₋₄alkyl.

In another embodiment, the present invention provides a compound ofFormula I**, wherein R₁ represents NR₇R₈, in which:

R₇ is selected from hydrogen, methyl, isopropyl, carboxy-ethyl,amino-propyl, tetrahydro-furan-2-ylmethyl, diisopropyl-amino-ethyl,benzo[1,3]dioxol-5-yl, phenyl, furanyl-methyl, benzyl, 1-phenyl-ethyl,pyridinyl, phenethyl, morpholino-propyl,3-(2-oxo-pyrrolidin-1-yl)-propyl, cycloheptyl, morpholino-ethyl,cyclopropyl, pyridinyl-ethyl; wherein any phenyl, benzyl, pyridinyl,phenethyl, morpholino, cyclopropyl, cycloheptyl, pyridinyl, furanyl andbenzo-dioxolyl is optionally substituted by 1 to 2 radicals selectedfrom methyl, dimethyl-amino, methyl-carbonyl-amino, morpholino,morpholino-methyl, morpholino-sulfonyl, methyl-piperazinyl,trifluoro-methyl, halo, methoxy, methyl-amino-carbonyl, amino-carbonyl,methyl-carbonyl-amino,

-   -   R₈ is hydrogen or R₇ and R₈ together with the nitrogen atom to        which R₇ and R₈ are attached form morpholino,    -   X₁ is oxygen and the other radicals and symbols have the same        meanings as provided for a compound of formula I** above.

In a further embodiment with respect to a compound of formula I**, R₃ isselected from hydrogen, methyl, 2-methoxy-1-methyl-ethyl,pyridinyl-methyl, pyridinyl-ethyl, morpholino, pyrrolidinyl-ethyl,phenethyl, morpholino-ethyl, morpholino-propyl,3-(2-oxo-pyrrolidin-1-yl)-propyl, cycloheptyl,3-(tetrahydro-furan-2-yl)-methyl, pyrrolidinyl-ethyl andpyrazinyl-methyl; wherein any alkyl, aryl, heteroaryl, cycloalkyl orheterocycloalkyl of R3 is optionally substituted by 1-3 radicalsselected from fluoro, methyl and amino-sulfonyl.

In another embodiment with respect to a compound of formula I**, s and rare both 1; R₃₅ is selected from methyl, methoxy and fluoro; and R₄₅ isselected from phenyl optionally substituted by trifluoromethyl,piperazinyl-methyl; wherein any piperazinyl substituent of R₄₅ isoptionally substituted by methyl.

In another embodiment, r is 0; s is selected from 1 or 2; and R₃₅ isselected from methoxy and trifluoromethyl.

Preferred compounds of formula I** are selected from:N-[4-Methyl-3-(3-methyl-3-{6-[(tetrahydro-furan-2-ylmethyl)-amino]-pyrimidin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide;N-(3-{3-[6-(Benzo[1,3]dioxol-5-ylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide;N-(3-{3-[6-(3-Dimethylamino-phenylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide;N-(3-{3-[6-(3-Acetylamino-phenylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide;N-(4-Methyl-3-{3-methyl-3-[6-(4-morpholin-4-yl-phenylamino)-pyrimidin-4-yl]-ureido}-phenyl)-3-trifluoromethyl-benzamide;N-[4-Methyl-3-(3-methyl-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide;N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-(2-morpholin-4-yl-ethyl)-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-(3-{3-(6-Amino-pyrimidin-4-yl)-3-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide;N-(4-Fluoro-3-{3-[6-(4-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-ureido}-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide;N-(3-{3-[6-(4-Chloro-benzylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide;N-{4-Methyl-3-[3-methyl-3-(6-phenethylamino-pyrimidin-4-yl)-ureido]-phenyl}-3-trifluoromethyl-benzamide;N-(3-{3-[6-(4-Methoxy-benzylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide;N-[4-Methyl-3-(3-methyl-3-{6-[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-pyrimidin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide;N-{4-Methyl-3-[3-methyl-3-(6-methylamino-pyrimidin-4-yl)-ureido]-phenyl}-3-trifluoromethyl-benzamide;N-(4-Methyl-3-{3-methyl-3-[6-(1-phenyl-ethylamino)-pyrimidin-4-yl]-ureido}-phenyl)-3-trifluoromethyl-benzamide;N-(4-Methyl-3-{3-methyl-3-[6-(3-morpholin-4-yl-propylamino)-pyrimidin-4-yl]-ureido}-phenyl)-3-trifluoromethyl-benzamide;N-{3-[3-(6-Cyclopentylamino-pyrimidin-4-yl)-3-methyl-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-(3-{3-[6-(2-Diisopropylamino-ethylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide;N-(4-Methyl-3-{3-methyl-3-[6-(2-pyridin-2-yl-ethylamino)-pyrimidin-4-yl]-ureido}-phenyl)-3-trifluoromethyl-benzamide;N-{3-[3-(6-Isopropylamino-pyrimidin-4-yl)-3-methyl-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-[3-(3-{6-[(Furan-2-ylmethyl)-amino]-pyrimidin-4-yl}-3-methyl-ureido)-4-methyl-phenyl]-3-trifluoromethyl-benzamide;N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-methyl-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-(3-{3-[6-(2-Amino-ethylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide;N-(3-(3-{6-[2-(4-Fluoro-phenyl)-ethylamino]-pyrimidin-4-yl}-3-methyl-ureido)-4-methyl-phenyl]-3-trifluoromethyl-benzamide;N-(3-{3-[6-(4-Fluoro-benzylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide;3-(6-{1-Methyl-3-[2-methyl-5-(3-trifluoromethyl-benzoylamino)-phenyl]-ureido}-pyrimidin-4-ylamino)-propionicacid;N-(3-{3-[6-(3-Amino-propylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide;N-[3-(3-{6-[2-(4-Methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-3-methyl-ureido)-4-methyl-phenyl]-3-trifluoromethyl-benzamide;N-(3-{3-[6-(6-Methoxy-pyridin-3-ylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide;N-(4-Methyl-3-{3-methyl-3-[6-(2-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-ureido}-phenyl)-3-trifluoromethyl-benzamide;N-[3-(3-{6-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-pyrimidin-4-yl}-3-methyl-ureido)-4-methyl-phenyl]-3-trifluoromethyl-benzamide;N-{4-Methyl-3-[3-methyl-3-(6-morpholin-4-yl-pyrimidin-4-yl)-ureido]-phenyl}-3-trifluoromethyl-benzamide;N-(4-Methyl-3-{3-methyl-3-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-ureido}-phenyl)-3-trifluoromethyl-benzamide;N-(4-Methyl-3-{3-methyl-3-[6-((3-methyl-amino-carbonyl-phenyl)-amino)-pyrimidin-4-yl]-ureido}-phenyl)-3-trifluoromethyl-benzamide;N-{3-[3-(6-Cyclopropylamino-pyrimidin-4-yl)-3-methyl-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-(4-Methyl-3-{3-methyl-3-[6-((4-amino-carbonyl-phenyl)-amino)-pyrimidin-4-yl]-ureido}-phenyl)-3-trifluoromethyl-benzamide;N-(3-{3-[6-(4-Acetylamino-phenylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide;N-[4-Methyl-3-(3-methyl-3-{6-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-pyrimidin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide;N-(4-Methyl-3-{3-methyl-3-[6-(3-morpholin-4-ylmethyl-phenylamino)-pyrimidin-4-yl]-ureido}-phenyl)-3-trifluoromethyl-benzamide;N-[4-Methyl-3-(3-methyl-3-{6-[3-(morpholine-4-sulfonyl)-phenylamino]-pyrimidin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide;N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-cyclopentyl-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-(tetrahydro-furan-2-ylmethyl)-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-(2-pyrrolidin-1-yl-ethyl)-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-(5-methyl-pyrazin-2-ylmethyl)-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-(2-methoxy-1-methyl-ethyl)-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-pyridin-2-ylmethyl-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-(2-pyridin-2-yl-ethyl)-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-morpholin-4-yl-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-(3-{3-(6-Amino-pyrimidin-4-yl)-3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide;N-(3-{3-(6-Amino-pyrimidin-4-yl)-3-[2-(4-sulfamoyl-phenyl)-ethyl]-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide;N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-(3-morpholin-4-yl-propyl)-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-(3-{3-(6-Amino-pyrimidin-4-yl)-3-[2-(2-fluoro-phenyl)-ethyl]-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide;N-{3-[3-[6-(2,6-Dimethyl-pyridin-3-ylamino)-pyrimidin-4-yl]-3-(2-morpholin-4-yl-ethyl)-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-{3-[3-[6-(4,6-Dimethyl-pyridin-3-ylamino)-pyrimidin-4-yl]-3-(2-morpholin-4-yl-ethyl)-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-{3-[3-(6-Amino-5-methyl-pyrimidin-4-yl)-3-(2-morpholin-4-yl-ethyl)-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-{3-[3-(6-Amino-2-methyl-pyrimidin-4-yl)-3-(2-morpholin-4-yl-ethyl)-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;1-(6-Amino-pyrimidin-4-yl)-3-(2,4-dimethoxy-phenyl)-1-(2-morpholin-4-yl-ethyl)-urea;1-(6-Amino-pyrimidin-4-yl)-3-(2,5-dimethoxy-phenyl)-1-(2-morpholin-4-yl-ethyl)-urea;1-(6-Amino-pyrimidin-4-yl)-3-(3,4-dimethoxy-phenyl)-1-(2-morpholin-4-yl-ethyl)-urea;1-(6-Amino-pyrimidin-4-yl)-3-(3,5-dimethoxy-phenyl)-1-(2-morpholin-4-yl-ethyl)-urea;1-(6-Amino-pyrimidin-4-yl)-3-(3,5-bis-trifluoromethyl-phenyl)-1-(2-morpholin-4-yl-ethyl)-urea;and1-(6-Amino-pyrimidin-4-yl)-3-(3,5-bis-trifluoromethyl-phenyl)-1-(2-morpholin-4-yl-ethyl)-thiourea.

Further preferred compounds of Formula I** are detailed in the Examplesand Table I, infra.

Compounds of Formula I** inhibit abl kinase, especially v-abl kinase.The compounds of Formula I** also inhibit wild-type BCR-Abl kinase andmutations of BCR-Abl kinase and are thus suitable for the treatment ofBcr-abl-positive cancer and tumor diseases, such as leukemias(especially chronic myeloid leukemia and acute lymphoblastic leukemia,where especially apoptotic mechanisms of action are found), and alsoshows effects on the subgroup of leukemic stem cells as well aspotential for the purification of these cells in vitro after removal ofsaid cells (for example, bone marrow removal) and reimplantation of thecells once they have been cleared of cancer cells (for example,reimplantation of purified bone marrow cells).

PDGF (Platelet-derived Growth Factor) is a very commonly occurringgrowth factor, which plays an important role both in normal growth andalso in pathological cell proliferation, such as is seen incarcinogenesis and in diseases of the smooth-muscle cells of bloodvessels, for example in atherosclerosis and thrombosis. Compounds ofFormula I** can inhibit PDGF receptor (PDGFR) activity and are,therefore, suitable for the treatment of tumor diseases, such asgliomas, sarcomas, prostate tumors, and tumors of the colon, breast, andovary.

Compounds of Formula I** can be used not only as a tumor-inhibitingsubstance, for example in small cell lung cancer, but also as an agentto treat non-malignant proliferative disorders, such as atherosclerosis,thrombosis, psoriasis, scleroderma and fibrosis, as well as for theprotection of stem cells, for example to combat the hemotoxic effect ofchemotherapeutic agents, such as 5-fluoruracil, and in asthma. Compoundsof Formula I** can especially be used for the treatment of diseases,which respond to an inhibition of the PDGF receptor kinase.

Compounds of Formula I** show useful effects in the treatment ofdisorders arising as a result of transplantation, for example, allogenictransplantation, especially tissue rejection, such as especiallyobliterative bronchiolitis (OB), i.e. a chronic rejection of allogeniclung transplants. In contrast to patients without OB, those with OBoften show an elevated PDGF concentration in bronchoalveolar lavagefluids.

Compounds of Formula I** are also effective in diseases associated withvascular smooth-muscle cell migration and proliferation (where PDGF andPDGF-R often also play a role), such as restenosis and atherosclerosis.These effects and the consequences thereof for the proliferation ormigration of vascular smooth-muscle cells in vitro and in vivo can bedemonstrated by administration of the compounds of the presentinvention, and also by investigating its effect on the thickening of thevascular intima following mechanical injury in vivo.

The compounds of Formula I** also inhibit cellular processes involvingstem-cell factor (SCF, also known as the c-kit ligand or steel factor),such as inhibiting SCF receptor (kit) autophosphorylation andSCF-stimulated activation of MAPK kinase (mitogen-activated proteinkinase). MO7e cells are a human promegakaryocytic leukemia cell line,which depends on SCF for proliferation. Compounds of the invention caninhibit the autophosphorylation of SCF receptors.

The trk family of neurotrophin receptors (trkA, trkB, trkC) promotes thesurvival, growth and differentiation of the neuronal and non-neuronaltissues. The TrkB protein is expressed in neuroendocrine-type cells inthe small intestine and colon, in the alpha cells of the pancreas, inthe monocytes and macrophages of the lymph nodes and of the spleen, andin the granular layers of the epidermis (Shibayama and Koizumi, 1996).Expression of the TrkB protein has been associated with an unfavorableprogression of Wilms tumors and of neuroblastomas. TkrB is, moreover,expressed in cancerous prostate cells but not in normal cells. Thesignaling pathway downstream of the trk receptors involves the cascadeof MAPK activation through the Shc, activated Ras, ERK-1 and ERK-2genes, and the PLC-gammal transduction pathway (Sugimoto et al., 2001).

The kinase, c-Src transmits oncogenic signals of many receptors. Forexample, over-expression of EGFR or HER3/neu in tumors leads to theconstitutive activation of c-src, which is characteristic for themalignant cell but absent from the normal cell. On the other hand, micedeficient in the expression of c-src exhibit an osteopetrotic phenotype,indicating a key participation of c-src in osteoclast function and apossible involvement in related disorders.

The Tec family kinase, Bmx, a non-receptor protein-tyrosine kinase,controls the proliferation of mammary epithelial cancer cells.

Fibroblast growth factor receptor 3 was shown to exert a negativeregulatory effect on bone growth and an inhibition of chondrocyteproliferation. Thanatophoric dysplasia is caused by different mutationsin fibroblast growth factor receptor 3, and one mutation, TDII FGFR35,has a constitutive tyrosine kinase activity which activates thetranscription factor Stat1, leading to expression of a cell-cycleinhibitor, growth arrest and abnormal bone development (Su et al.,Nature, 1997, 386, 288-292). FGFR35 is also often expressed in multiplemyeloma-type cancers.

The activity of serum and glucocorticoid-regulated kinase (SGK), iscorrelated to perturbed ion-channel activities, in particular, those ofsodium and/or potassium channels and compounds of the invention can beuseful for treating hypertension.

Lin et al (1997) J. Clin. Invest. 100, 8: 2072-2078 and P. Lin (1998)PNAS 95, 8829-8834, have shown an inhibition of tumor growth andvascularization and also a decrease in lung metastases during adenoviralinfections or during injections of the extracellular domain of Tie-2(Tek) in breast tumor and melanoma xenograft models. Tie2 inhibitors canbe used in situations where neovascularization takes placeinappropriately (i.e. in diabetic retinopathy, chronic inflammation,psoriasis, Kaposi's sarcoma, chronic neovascularization due to maculardegeneration, rheumatoid arthritis, infantile haemangioma and cancers).

Lck plays a role in T-cell signaling. Mice that lack the Lck gene have apoor ability to develop thymocytes. The function of Lck as a positiveactivator of T-cell signaling suggests that Lck inhibitors may be usefulfor treating autoimmune disease such as rheumatoid arthritis.

JNKs, along with other MAPKs, have been implicated in having a role inmediating cellular response to cancer, thrombin-induced plateletaggregation, immunodeficiency disorders, autoimmune diseases, celldeath, allergies, osteoporosis and heart disease. The therapeutictargets related to activation of the JNK pathway include chronicmyelogenous leukemia (CML), rheumatoid arthritis, asthma,osteoarthritis, ischemia, cancer and neurodegenerative diseases. As aresult of the importance of JNK activation associated with liver diseaseor episodes of hepatic ischemia, compounds of the invention may also beuseful to treat various hepatic disorders. A role for JNK incardiovascular disease such as myocardial infarction or congestive heartfailure has also been reported as it has been shown JNK mediateshypertrophic responses to various forms of cardiac stress. It has beendemonstrated that the JNK cascade also plays a role in T-cellactivation, including activation of the IL-2 promoter.

Thus, inhibitors of JNK may have therapeutic value in alteringpathologic immune responses. A role for JNK activation in variouscancers has also been established, suggesting the potential use of JNKinhibitors in cancer. For example, constitutively activated JNK isassociated with HTLV-1 mediated tumorigenesis [Oncogene 13:135-42(1996)]. JNK may play a role in Kaposi's sarcoma (KS). Otherproliferative effects of other cytokines implicated in KS proliferation,such as vascular endothelial growth factor (VEGF), IL-6 and INFO, mayalso be mediated by JNK. In addition, regulation of the c-jun gene inp210 BCR-ABL transformed cells corresponds with activity of JNK,suggesting a role for JNK inhibitors in the treatment for chronicmyelogenous leukemia (CML) [Blood 92:2450-60 (1998)].

Certain abnormal proliferative conditions are believed to be associatedwith raf expression and are, therefore, believed to be responsive toinhibition of raf expression. Abnormally high levels of expression ofthe raf protein are also implicated in transformation and abnormal cellproliferation. These abnormal proliferative conditions are also believedto be responsive to inhibition of raf expression. For example,expression of the c-raf protein is believed to play a role in abnormalcell proliferation since it has been reported that 60% of all lungcarcinoma cell lines express unusually high levels of c-raf mRNA andprotein. Further examples of abnormal proliferative conditions arehyper-proliferative disorders such as cancers, tumors, hyperplasia,pulmonary fibrosis, angiogenesis, psoriasis, atherosclerosis and smoothmuscle cell proliferation in the blood vessels, such as stenosis orrestenosis following angioplasty. The cellular signaling pathway ofwhich raf is a part has also been implicated in inflammatory disorderscharacterized by T-cell proliferation (T-cell activation and growth),such as tissue graft rejection, endotoxin shock, and glomerularnephritis, for example.

The stress activated protein kinases (SAPKs) are a family of proteinkinases that represent the penultimate step in signal transductionpathways that result in activation of the c-jun transcription factor andexpression of genes regulated by c-jun. In particular, c-jun is involvedin the transcription of genes that encode proteins involved in therepair of DNA that is damaged due to genotoxic insults. Therefore,agents that inhibit SAPK activity in a cell prevent DNA repair andsensitize the cell to agents that induce DNA damage or inhibit DNAsynthesis and induce apoptosis of a cell or that inhibit cellproliferation.

Mitogen-activated protein kinases (MAPKs) are members of conservedsignal transduction pathways that activate transcription factors,translation factors and other target molecules in response to a varietyof extracellular signals. MAPKs are activated by phosphorylation at adual phosphorylation motif having the sequence Thr-X-Tyr bymitogen-activated protein kinase kinases (MKKs). In higher eukaryotes,the physiological role of MAPK signaling has been correlated withcellular events such as proliferation, oncogenesis, development anddifferentiation. Accordingly, the ability to regulate signaltransduction via these pathways (particularly via MKK4 and MKK6) couldlead to the development of treatments and preventive therapies for humandiseases associated with MAPK signaling, such as inflammatory diseases,autoimmune diseases and cancer.

In accordance with the foregoing, the present invention further providesa method for preventing or treating any of the diseases or disordersdescribed above in a subject in need of such treatment, which methodcomprises administering to said subject a therapeutically effectiveamount (See, “Administration and Pharmaceutical Compositions”, infra) ofa compound of Formula I** or a pharmaceutically acceptable salt thereof.For any of the above uses, the required dosage will vary depending onthe mode of administration, the particular condition to be treated andthe effect desired.

In general, compounds of Formula I** will be administered intherapeutically effective amounts via any of the usual and acceptablemodes known in the art, either singly or in combination with one or moretherapeutic agents. A therapeutically effective amount may vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors. Ingeneral, satisfactory results are indicated to be obtained systemicallyat daily dosages of from about 0.03 to 2.5 mg/kg per body weight. Anindicated daily dosage in the larger mammal, e.g. humans, is in therange from about 0.5 mg to about 100 mg, conveniently administered, e.g.in divided doses up to four times a day or in retard form. Suitable unitdosage forms for oral administration comprise from ca. 1 to 50 mg activeingredient.

Compounds of Formula I** can be administered as pharmaceuticalcompositions by any conventional route, in particular enterally, e.g.,orally, e.g., in the form of tablets or capsules, or parenterally, e.g.,in the form of injectable solutions or suspensions, topically, e.g., inthe form of lotions, gels, ointments or creams, or in a nasal orsuppository form. Pharmaceutical compositions comprising a compound ofthe present invention in free form or in a pharmaceutically acceptablesalt form in association with at least one pharmaceutically acceptablecarrier or diluent can be manufactured in a conventional manner bymixing, granulating or coating methods. For example, oral compositionscan be tablets or gelatin capsules comprising the active ingredienttogether with a) diluents, e.g., lactose, dextrose, sucrose, mannitol,sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum,stearic acid, its magnesium or calcium salt and/or polyethyleneglycol;for tablets also c) binders, e.g., magnesium aluminum silicate, starchpaste, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose and or polyvinylpyrrolidone; if desired d)disintegrants, e.g., starches, agar, alginic acid or its sodium salt, oreffervescent mixtures; and/or e) absorbents, colorants, flavors andsweeteners. Injectable compositions can be aqueous isotonic solutions orsuspensions, and suppositories can be prepared from fatty emulsions orsuspensions. The compositions may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. In addition, they may also contain other therapeuticallyvaluable substances. Suitable formulations for transdermal applicationsinclude an effective amount of a compound of the present invention witha carrier. A carrier can include absorbable pharmacologically acceptablesolvents to assist passage through the skin of the host. For example,transdermal devices are in the form of a bandage comprising a backingmember, a reservoir containing the compound optionally with carriers,optionally a rate controlling barrier to deliver the compound to theskin of the host at a controlled and predetermined rate over a prolongedperiod of time, and means to secure the device to the skin. Matrixtransdermal formulations may also be used. Suitable formulations fortopical application, e.g., to the skin and eyes, are preferably aqueoussolutions, ointments, creams or gels well-known in the art. Such maycontain solubilizers, stabilizers, tonicity enhancing agents, buffersand preservatives.

Compounds of Formula I** can be administered in therapeuticallyeffective amounts in combination with one or more therapeutic agents(pharmaceutical combinations). For example, synergistic effects canoccur with other immunomodulatory or anti-inflammatory substances, forexample when used in combination with cyclosporin, rapamycin, orascomycin, or immunosuppressant analogues thereof, for examplecyclosporin A (CsA), cyclosporin G, FK-506, rapamycin, or comparablecompounds, corticosteroids, cyclophosphamide, azathioprine,methotrexate, brequinar, leflunomide, mizoribine, mycophenolic acid,mycophenolate mofetil, 15-deoxyspergualin, immunosuppressant antibodies,especially monoclonal antibodies for leukocyte receptors, for exampleMHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD45, CD58 or their ligands, orother immunomodulatory compounds, such as CTLA41g. Where the compoundsof the invention are administered in conjunction with other therapies,dosages of the co-administered compounds will of course vary dependingon the type of co-drug employed, on the specific drug employed, on thecondition being treated and so forth.

The invention also provides for a pharmaceutical combinations, e.g. akit, comprising a) a first agent which is a compound of Formula I** asdisclosed herein, in free form or in pharmaceutically acceptable saltform, and b) at least one co-agent. The kit can comprise instructionsfor its administration.

The terms “co-administration” or “combined administration” or the likeas utilized herein are meant to encompass administration of the selectedtherapeutic agents to a single patient, and are intended to includetreatment regimens in which the agents are not necessarily administeredby the same route of administration or at the same time.

The term “pharmaceutical combination” as used herein means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of Formula I** and a co-agent, are bothadministered to a patient simultaneously in the form of a single entityor dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound of Formula I** and a co-agent, are bothadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific time limits, wherein suchadministration provides therapeutically effective levels of the 2compounds in the body of the patient. The latter also applies tococktail therapy, e.g. the administration of 3 or more activeingredients.

The present invention also includes processes for the preparation ofcompounds of Formula I**. In the reactions described herein, it can benecessary to protect reactive functional groups, for example hydroxy,amino, imino, thio or carboxy groups, where these are desired in thefinal product, to avoid their unwanted participation in the reactions.Conventional protecting groups can be used in accordance with standardpractice, for example, see T. W. Greene and P. G. M. Wuts in “ProtectiveGroups in Organic Chemistry”, John Wiley and Sons, 1991.

Detailed examples of the synthesis of a compound of Formula I** can befound in the Examples, infra. The examples include solid phase synthesisof compounds of Formula I**.

A compound of Formula (I) (or exemplary formula thereof) can beadministered alone or in combination with one or more other therapeuticagents, possible combination therapy taking the form of fixedcombinations or the administration of a compound of the invention andone or more other therapeutic agents being staggered or givenindependently of one another, or the combined administration of fixedcombinations and one or more other therapeutic agents. A compound ofFormula (I) (or exemplary formula thereof) can besides or in addition beadministered especially for tumor therapy, such as leukaemia therapy, incombination with chemotherapy, radiotherapy, immunotherapy, surgicalintervention, or a combination of these. Long-term therapy is equallypossible as is adjuvant therapy in the context of other treatmentstrategies, as described above. Other possible treatments are therapy tomaintain the patient's status after tumor regression, or evenchemopreventive therapy, for example in patients at risk.

Therapeutic agents for possible combination are especially one or morecytostatic or cytotoxic compounds, for example a chemotherapeutic agentor several selected from the group comprising indarubicin, cytarabine,interferon, hydroxyurea, bisulfan, or an inhibitor of polyaminebiosynthesis, an inhibitor of protein kinase, especially ofserine/threonine protein kinase, such as protein kinase C, or oftyrosine protein kinase, such as epidermal growth factor receptortyrosine kinase, a cytokine, a negative growth regulator, such as TGF-βor IFN-β, an aromatase inhibitor, a classical cytostatic, and aninhibitor of the interaction of an SH2 domain with a phosphorylatedprotein. A specific example of a combination agent is(N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine(Glivec®/Gleevec®).

A compound according to the invention is not only for the (prophylacticand preferably therapeutic) management of humans, but also for thetreatment of other warm-blooded animals, for example of commerciallyuseful animals, for example rodents, such as mice, rabbits or rats, orguinea-pigs. Such a compound may also be used as a reference standard inthe test systems described above to permit a comparison with othercompounds.

In general, the invention relates also to the use of a compound ofFormula (I) (or exemplary formula thereof) or a N-oxide thereof for theinhibition of tyrosine kinase activity, either in vitro or in vivo.

With the groups of preferred compounds of Formula (I) (or exemplaryformula thereof) and N-oxides thereof, definitions of substituents fromthe general definitions mentioned hereinbefore may reasonably be used,for example, to replace more general definitions with more specificdefinitions or especially with definitions characterized as beingpreferred.

Especially, the invention relates to the use of a compound of Formula(I) (or exemplary formula thereof) or of a N-oxide or a possibletautomer thereof or of a pharmaceutically acceptable salt of such acompound for the preparation of a pharmaceutical composition for thetreatment of a disease which responds to an inhibition of protein kinaseactivity, wherein the disease is a neoplastic disease.

More particularly, the invention relates to the use of a compound oftheFormula (I) (or exemplary formula thereof) or of a N-oxide or apossible tautomer thereof; or of a pharmaceutically acceptable salt ofsuch a compound for the preparation of a pharmaceutical composition forthe treatment of leukaemia which responds to an inhibition of the Abl,Abl-Bcr, including mutant forms thereof, and VEGF-R2 tyrosine kinaseactivity.

Particular active products are compounds named in the examples andsalts, esters, N-oxides or prodrugs thereof.

In addition, the invention provides a method for the treatment of adisease which responds to an inhibition of protein kinase activity,which comprises administering a compound of Formula (I) (or exemplaryformula thereof) or a N-oxide or a pharmaceutically acceptable saltthereof, wherein the radicals and symbols have the meanings as definedabove, in a quantity effective against said disease, to a warm-bloodedanimal requiring such treatment.

A compound of the invention may be prepared by processes that, thoughnot applied hitherto for the new compounds of the present invention, areknown per se, where the compounds and intermediates may also be presentwith functional groups in protected form if necessary and/or in the formof salts, provided a salt-forming group is present and the reaction insalt form is possible;

any protecting groups in a protected derivative of a compound of theFormula (I) (or exemplary formula thereof) are removed;and, if so desired, an obtainable compound of Formula (I) (or exemplaryformula thereof) is converted into another compound of Formula (I) (orexemplary formula thereof) or a N-oxide thereof, a free compound ofFormula (I) (or exemplary formula thereof) is converted into a salt, anobtainable salt of a compound of Formula (I) (or exemplary formulathereof) is converted into the free compound or another salt, and/or amixture of isomeric compounds of Formula (I) (or exemplary formulathereof) is separated into the individual isomers.

Compounds of the invention in unoxidized form can be prepared fromN-oxides of compounds of the invention by treating with a reducing agent(e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride,sodium borohydride, phosphorus trichloride, tribromide, or the like) ina suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueousdioxane, or the like) at 0 to 80° C.

Prodrug derivatives of the compounds of the invention can be prepared bymethods known to those of ordinary skill in the art (e.g., for furtherdetails see Saulnier et al., (1994), Bioorganic and Medicinal ChemistryLetters, Vol. 4, p. 1985). For example, appropriate prodrugs can beprepared by reacting a non-derivatized compound of the invention with asuitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate,para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of the invention can be made bymeans known to those of ordinary skill in the art. A detaileddescription of techniques applicable to the creation of protectinggroups and their removal can be found in T. W. Greene, “ProtectingGroups in Organic Chemistry”, 3^(rd) edition, John Wiley and Sons, Inc.,1999.

Compounds of the present invention can be conveniently prepared, orformed during the process of the invention, as solvates (e.g.,hydrates). Hydrates of compounds of the present invention can beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Compounds of the invention can be prepared as their individualstereoisomers by reacting a racemic mixture of the compound with anoptically active resolving agent to form a pair of diastereoisomericcompounds, separating the diastereomers and recovering the opticallypure enantiomers. While resolution of enantiomers can be carried outusing covalent diastereomeric derivatives of the compounds of theinvention, dissociable complexes are preferred (e.g., crystallinediastereomeric salts). Diastereomers have distinct physical properties(e.g., melting points, boiling points, solubilities, reactivity, etc.)and can be readily separated by taking advantage of thesedissimilarities. The diastereomers can be separated by chromatography,or preferably, by separation/resolution techniques based upondifferences in solubility. The optically pure enantiomer is thenrecovered, along with the resolving agent, by any practical means thatwould not result in racemization. A more detailed description of thetechniques applicable to the resolution of stereoisomers of compoundsfrom their racemic mixture can be found in Jean Jacques, Andre Collet,Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John WileyAnd Sons, Inc., 1981.

Insofar as the production of the starting materials is not particularlydescribed, the compounds are known or can be prepared analogously tomethods known in the art or as disclosed in the Examples hereinafter.

One of skill in the art will appreciate that the above transformationsare only representative of methods for preparation of the compounds ofthe present invention, and that other well known methods can similarlybe used.

Protecting Groups

If one or more other functional groups, for example carboxy, hydroxy,amino, or mercapto, are or need to be protected in a compound of Formula(I) (or exemplary formula thereof)II, because they should not take partin the reaction, these are such groups as are usually used in thesynthesis of amides, in particular peptide compounds, and also ofcephalosporins and penicillins, as well as nucleic acid derivatives andsugars.

The protecting groups may already be present in precursors and shouldprotect the functional groups concerned against unwanted secondaryreactions, such as acylations, etherifications, esterifications,oxidations, solvolysis, and similar reactions. It is a characteristic ofprotecting groups that they lend themselves readily, i.e. withoutundesired secondary reactions, to removal, typically by solvolysis,reduction, photolysis or also by enzyme activity, for example underconditions analogous to physiological conditions, and that they are notpresent in the end-products. The specialist knows, or can easilyestablish, which protecting groups are suitable with the reactionsmentioned hereinabove and hereinafter.

The protection of such functional groups by such protecting groups, theprotecting groups themselves, and their removal reactions are describedfor example in standard reference books for peptide synthesis as citedhereinbefore, and in special books on protective groups such as J. F. W.McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, Londonand New York 1973, in “Methoden der organischen Chemie” (Methods oforganic chemistry), Houben-Weyl, 4th edition, Volume 15/1, Georg ThiemeVerlag, Stuttgart 1974, and in T. W. Greene, “Protective Groups inOrganic Synthesis”, Wiley, New York.

Pharmaceutical Preparations, Methods, and Uses

The present invention relates also to pharmaceutical compositions thatcomprise a compound of Formula (I) (or exemplary formula thereof) or aN-oxide thereof as active ingredient and that can be used especially inthe treatment of the aforementioned diseases.

The pharmacologically acceptable compounds of the present invention maybe used, for ex-ample, for the preparation of pharmaceuticalcompositions that comprise a pharmaceutically effective amount of acompound of the Formula (I) (or exemplary formula thereof), or apharmaceutically acceptable salt thereof, as active ingredient togetheror in admixture with a significant amount of one or more inorganic ororganic, solid or liquid, pharmaceutically acceptable carriers.

The invention relates also to a pharmaceutical composition that issuitable for administration to a warm-blooded animal, especially a human(or to cells or cell lines derived from a warm-blooded animal,especially a human, e.g. lymphocytes), for the treatment or, in abroader aspect of the invention, prevention of (=prophylaxis against) adisease that responds to inhibi-tion of tyrosin protein kinase activity,especially one of the diseases mentioned above as being preferred foruse of a compound of Formula (I) (or exemplary formula thereof),comprising an amount of a novel compound of Formula (I) (or exemplaryformula thereof), or a pharmaceutically acceptable salt thereof, whichis effective for said inhibition, together with at least onepharmaceutically acceptable carrier.

Compositions for enteral administration, such as nasal, buccal, rectalor, especially, oral administration, and for parenteral administration,such as intravenous, intramuscular or subcutaneous administration, towarm-blooded animals, especially humans, are especially preferred. Thecompositions comprise the active ingredient alone or, preferably,together with a pharmaceutically acceptable carrier. The dosage of theactive ingredient depends upon the disease to be treated and upon thespecies, its age, weight, and individual condition, the individualpharmacokinetic data, and the mode of administration.

The present invention relates especially to pharmaceutical compositionsthat comprise a compound of Formula (I) (or exemplary formula thereof),a tautomer, a N-oxide or a pharmaceutically acceptable salt, or ahydrate or solvate thereof, and at least one pharmaceutically acceptablecarrier.

The invention relates also to pharmaceutical compositions for use in amethod for the pro-phylactic or especially therapeutic management of thehuman or animal body, to a process for the preparation thereof(especially in the form of compositions for the treatment of tumors) andto a method of treating tumor diseases, especially those mentionedhereinabove.

The invention relates also to processes and to the use of compounds ofFormula (I) (or exemplary formula thereof) or N-oxides thereof for thepreparation of pharmaceutical preparations which comprise compounds ofFormula (I) (or exemplary formula thereof) or N-oxides thereof as activecomponent (active ingredient).

The pharmaceutical compositions comprise from approximately 1% toapproximately 95% active ingredient, single-dose administration formscomprising in the preferred embodiment from approximately 20% toapproximately 90% active ingredient and forms that are not ofsingle-dose type comprising in the preferred embodiment fromapproximately 5% to approximately 20% active ingredient. Unit dose formsare, for example, coated and uncoated tablets, ampoules, vials,suppositories, or capsules. Further dosage forms are, for example,ointments, creams, pastes, foams, tinctures, sprays, etc. Examples arecapsules containing from about 0.05 g to about 1.0 g active ingredient.

The pharmaceutical compositions of the present invention are prepared ina manner known per se, for example by means of conventional mixing,granulating, coating, dissolving or lyophilizing processes.

Preference is given to the use of solutions of the active ingredient,and also suspensions or dispersions, especially isotonic aqueoussolutions, dispersions or suspensions which, for example in the case oflyophilized compositions comprising the active ingredient alone ortogether with a carrier can be made up before use. The pharmaceuticalcompositions may be sterilized and/or may comprise excipients, forexample preservatives, stabilizers, wetting agents and/or emulsifiers,solubilizers, salts for regulating osmotic pressure and/or buffers andare prepared in a manner known per se, for example by means ofconventional dissolving and lyophilizing processes. The said solutionsor suspensions may comprise viscosity-increasing agents or solubilizers,such as sodium carboxymethylcellulose, carboxy-methylcellulose, dextran,polyvinylpyrrolidone or gelatin.

Suspensions in oil comprise as the oil component the vegetable,synthetic or semi-synthetic oils customary for injection purposes. Theremay be mentioned as such especially liquid fatty acid esters thatcontain as the acid component a long-chained fatty acid having from 8 to22, especially from 12 to 22, carbon atoms, for example lauric acid,tridecylic acid, myristic acid, pentadecylic acid, palmitic acid,margaric acid, stearic acid, arachidic acid, behenic acid orcorresponding unsaturated acids, for example oleic acid, elaidic acid,erucic acid, brasidic acid or linoleic acid, if desired with theaddition of antioxidants, for example vitamin E, β-carotene or3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of those fattyacid esters has a maximum of 6 carbon atoms and is a mono- orpoly-hydroxy, for example a mono-, di- or tri-hydroxy, alcohol, forexample methanol, ethanol, propanol, butanol or pentanol or the isomersthereof, but especially glycol and glycerol. The following examples offatty acid esters are therefore to be mentioned: ethyl oleate, isopropylmyristate, isopropyl palmitate, “Labrafil M 2375” (polyoxyethyleneglycerol trioleate, Gattefosse, Paris), “Miglyol 812” (tri-glyceride ofsaturated fatty acids with a chain length of C₈ to C₁₂, Hüls AG,Germany), but especially vegetable oils, such as cottonseed oil, almondoil, olive oil, castor oil, sesame oil, soybean oil and more especiallygroundnut oil.

Injection compositions are prepared in customary manner under sterileconditions; the same applies also to introducing the compositions intoampoules or vials and sealing the con-tainers.

Pharmaceutical compositions for oral administration can be obtained bycombining the active ingredient with solid carriers, if desiredgranulating a resulting mixture, and processing the mixture, if desiredor necessary, after the addition of appropriate excipients, intotablets, dra-gee cores or capsules. It is also possible for them to beincorporated into plastics carriers that allow the active ingredients todiffuse or be released in measured amounts.

Suitable carriers are especially fillers, such as sugars, for examplelactose, saccharose, mannitol or sorbitol, cellulose preparations and/orcalcium phosphates, for example trical-cium phosphate or calciumhydrogen phosphate, and binders, such as starch pastes using for examplecorn, wheat, rice or potato starch, gelatin, tragacanth,methylcellulose, hydro-xypropylmethylcellulose, sodiumcarboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired,disintegrators, such as the above-mentioned starches, and/orcarboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginicacid or a salt thereof, such as sodium alginate. Excipients areespecially flow conditioners and lubricants, for example silicic acid,talc, stearic acid or salts thereof, such as magnesium or calciumstearate, and/or polyethyl-lene glycol. Dragée cores are provided withsuitable, optionally enteric, coatings, there being used, inter alia,concentrated sugar solutions which may comprise gum arabic, talc,polyvi-nylpyrrolidone, polyethylene glycol and/or titanium dioxide, orcoating solutions in suitable organic solvents, or, for the preparationof enteric coatings, solutions of suitable cellulose preparations, suchas ethylcellulose phthalate or hydroxypropylmethylcellulose phthalate.Capsules are dry-filled capsules made of gelatin and soft sealedcapsules made of gelatin and a plasticiser, such as glycerol orsorbitol. The dry-filled capsules may comprise the active ingredient inthe form of granules, for example with fillers, such as lactose,binders, such as starches, and/or glidants, such as talc or magnesiumstearate, and if desired with stabili-sers. In soft capsules the activeingredient is preferably dissolved or suspended in suitable oilyexcipients, such as fatty oils, paraffin oil or liquid polyethyleneglycols, it being possible also for stabilisers and/or antibacterialagents to be added. Dyes or pigments may be added to the tablets ordragée coatings or the capsule casings, for example for identificationpur-poses or to indicate different doses of active ingredient.

Tablet cores can be provided with suitable, optionally enteric, coatingsthrough the use of, inter alia, concentrated sugar solutions which maycomprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycoland/or titanium dioxide, or coating solutions in suitable organicsolvents or solvent mixtures, or, for the preparation of entericcoatings, solutions of suitable cellulose preparations.

Pharmaceutical compositions for oral administration also include hardcapsules consisting of gelatin, and also soft, sealed capsulesconsisting of gelatin and a plasticizer. The hard capsules may containthe active ingredient in the form of granules, for example in admixturewith fillers, binders, and/or glidants, and optionally stabilizers. Insoft capsules, the active ingredient is preferably dissolved orsuspended in suitable liquid excipients, to which stabilizers anddetergents may also be added.

Pharmaceutical compositions suitable for rectal administration are, forexample, suppositories that consist of a combination of the activeingredient and a suppository base.

For parenteral administration, aqueous solutions of an active ingredientin water-soluble form, for example of a water-soluble salt, or aqueousinjection suspensions that contain viscosity-increasing substances, forexample sodium carboxymethylcellulose, sorbitol and/or dextran, and, ifdesired, stabilizers, are especially suitable. The active ingredient,optionally together with excipients, can also be in the form of alyophilizate and can be made into a solution before parenteraladministration by the addition of suitable solvents.

Solutions such as are used, for example, for parenteral administrationcan also be employed as infusion solutions.

The invention relates likewise to a process or a method for thetreatment of one of the pathological conditions mentioned hereinabove,especially a disease which responds to an inhibition of a tyrosinekinase, especially a corresponding neoplastic disease. The compounds ofFormula (I) (or exemplary formula thereof) or N-oxides thereof can beadministered as such or especially in the form of pharmaceuticalcompositions, prophylactically or therapeutically, preferably in anamount effective against the said diseases, to a warm-blooded animal,for example a human, requiring such treatment. In the case of anindividual having a bodyweight of about 70 kg the daily doseadministered is from approximately 0.05 g to approximately 5 g,preferably from approximately 0.25 g to approximately 1.5 g, of acompound of the present invention.

The invention also provides for a method of treating a protein kinasedependent disease, comprising administering to a warm-blooded animal,for example a human, one or more cytostatic or cytotoxic compounds e.g.Glivec® in combination with a compound of the invention, whether at thesame time, or a separate time. The term the same time is taken to meanin quick succession or immediately after one another.

The present invention relates especially also to the use of a compoundof Formula (I) (or exemplary formula thereof) or N-oxides thereof, or apharmaceutically acceptable salt thereof, especially a compound ofFormula (I) (or exemplary formula thereof) which is said to bepreferred, or a pharmaceutically acceptable salt thereof, as such or inthe form of a pharmaceutical formulation with at least onepharmaceutically acceptable carrier for the therapeutic and alsoprophylactic management of one or more of the diseases mentionedhereinabove, preferably a disease which responds to an inhibition of aprotein kinase, especially a neoplastic disease, more especiallyleukaemia which responds to an inhibition of the Abl tyrosine kinase.

The preferred dose quantity, composition, and preparation ofpharmaceutical formulations (medicines) which are to be used in eachcase are described above.

A compound of the Formula (I) (or exemplary formula thereof) may also beused to advantage in combination with other antiproliferative agents.Such antiproliferative agents include, but are not limited to aromataseinhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase IIinhibitors, microtubule active agents, alkylating agents, histonedeacetylase inhibitors, farnesyl transferase inhibitors, COX-2inhibitors, MMP inhibitors, mTOR inhibitors, antineoplasticantimetabolites, platin compounds, compounds decreasing the proteinkinase activity and further anti-angiogenic compounds, gonadorelinagonists, anti-androgens, bengamides, bisphosphonates, antiproliferativeantibodies and temozolomide (TEMODAL®).

The term “aromatase inhibitors” as used herein relates to compoundswhich inhibit the estrogen production, i.e. the conversion of thesubstrates androstenedione and testosterone to estrone and estradiol,respectively. The term includes, but is not limited to steroids,especially exemestane and formestane and, in particular, non-steroids,especially aminoglutethimide, vorozole, fadrozole, anastrozole and, veryespecially, letrozole. Exemestane can be administered, e.g., in the formas it is marketed, e.g. under the trademark AROMASIN™. Formestane can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark LENTARON™. Fadrozole can be administered, e.g., in the form asit is marketed, e.g. under the trademark AFEMA™. Anastrozole can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark ARIMIDEX™. Letrozole can be administered, e.g., in the form asit is marketed, e.g. under the trademark FEMARA™ or FEMAR™.Aminoglutethimide can be administered, e.g., in the form as it ismarketed, e.g. under the trademark ORIMETEN™.

A combination of the invention comprising an antineoplastic agent whichis an aromatase inhibitor is particularly useful for the treatment ofhormone receptor positive breast tumors. The term “antiestrogens” asused herein relates to compounds which antagonize the effect ofestrogens at the estrogen receptor level. The term includes, but is notlimited to tamoxifen, fulvestrant, raloxifene and raloxifenehydrochloride. Tamoxifen can be administered, e.g., in the form as it ismarketed, e.g. under the trademark NOLVADEX™. Raloxifene hydrochloridecan be administered, e.g., in the form as it is marketed, e.g. under thetrademark EVISTA™. Fulvestrant can be Formulated as disclosed in U.S.Pat. No. 4,659,516 or it can be administered, e.g., in the form as it ismarketed, e.g. under the trademark FASLODEX™.

The term “topoisomerase I inhibitors” as used herein includes, but isnot limited to topotecan, irinotecan, 9-nitrocamptothecin and themacromolecular camptothecin conjugate PNU-166148 (compound A1 inWO99/17804). Irinotecan can be administered, e.g., in the form as it ismarketed, e.g. under the trademark CAMPTOSAR™. Topotecan can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark HYCAMTIN™.

The term “topoisomerase II inhibitors” as used herein includes, but isnot limited to the antracyclines doxorubicin (including liposomalFormulation, e.g. CAELYX™), epirubicin, idarubicin and nemorubicin, theanthraquinones mitoxantrone and losoxantrone, and the podophillotoxinesetoposide and teniposide. Etoposide can be administered, e.g., in theform as it is marketed, e.g. under the trademark ETOPOPHOS™. Teniposidecan be administered, e.g., in the form as it is marketed, e.g. under thetrademark VM 26-BRISTOL™. Doxorubicin can be administered, e.g., in theform as it is marketed, e.g. under the trademark ADRIBLASTIN™.Epirubicin can be administered, e.g., in the form as it is mar-keted,e.g. under the trademark FARMORUBICIN™. Idarubicin can be administered,e.g., in the form as it is marketed, e.g. under the trademark ZAVEDOS™.Mitoxantrone can be administered, e.g., in the form as it is marketed,e.g. under the trademark NOVANTRON™.

The term “microtubule active agents” relates to microtubule stabilizingand microtubule destabilizing agents including, but not limited to thetaxanes paclitaxel and docetaxel, the vinca alkaloids, e.g.,vinblastine, especially vinblastine sulfate, vincristine especiallyvincristine sulfate, and vinorelbine, discodermolide and epothilones,such as epothilone B and D. Docetaxel can be administered, e.g., in theform as it is marketed, e.g. under the trademark TAXOTERE™. Vinblastinesulfate can be administered, e.g., in the form as it is marketed, e.g.under the trademark VINBLASTIN R.P.™ Vincristine sulfate can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark FARMISTIN™.

The term “alkylating agents” as used herein includes, but is not limitedto cyclophosphamide, ifosfamide and melphalan. Cyclophosphamide can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark CYCLOSTIN™. Ifosfamide can be administered, e.g., in the formas it is marketed, e.g. under the trademark HOLOXAN™.

The term “histone deacetylase inhibitors” relates to compounds whichinhibit the histone deacetylase and which possess antiproliferativeactivity.

The term “farnesyl transferase inhibitors” relates to compounds whichinhibit the farnesyl transferase and which possess antiproliferativeactivity.

The term “COX-2 inhibitors” relates to compounds which inhibit thecyclooxygenase type 2 enyzme (COX-2) and which possess antiproliferativeactivity such as celecoxib (Celebrex®), rofecoxib (Vioxx®) andlumiracoxib (COX189).

The term “MMP inhibitors” relates to compounds which inhibit the matrixmetalloproteinase (MMP) and which possess antiproliferative activity.

The term “mTOR inhibitors” relates to compounds which inhibit themammalian target of rapamycin (mTOR) and which possess antiproliferativeactivity such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779and ABT578.

The term “antineoplastic antimetabolites” includes, but is not limitedto 5-fluorouracil, tegafur, capecitabine, cladribine, cytarabine,fludarabine phosphate, fluorouridine, gemcitabine, 6-mercaptopurine,hydroxyurea, methotrexate, edatrexate and salts of such compounds, andfurthermore ZD 1694 (RALTITREXED™), LY231514 (ALIMTA™), LY264618(LOMOTREXOL™) and OGT719.

The term “platin compounds” as used herein includes, but is not limitedto carboplatin, cis-platin and oxaliplatin. Carboplatin can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark CARBOPLAT™. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark ELOXATIN™.

The term “compounds decreasing the protein kinase activity and furtheranti-angiogenic compounds” as used herein includes, but is not limitedto compounds which decrease the activity of e.g. the VascularEndothelial Growth Factor (VEGF), the Epidermal Growth Factor (EGF),c-Src, protein kinase C, the Platelet-derived Growth Factor (PDGF),Bcr-Abl, c-Kit, Flt-3, the Insulin-like Growth Factor I Receptor(IGF-IR) and the Cyclin-dependent kinases (CDKs), and anti-angiogeniccompounds having another mechanism of action than decreasing the proteinkinase activity.

Compounds which decrease the activity of VEGF are especially compoundswhich inhibit the VEGF receptor, especially the tyrosine kinase activityof the VEGF receptor, and compounds binding to VEGF, and are inparticular those compounds, proteins and monoclonal antibodiesgenerically and specifically disclosed in WO 98/35958, WO 00/09495, WO00/27820, WO 00/59509, WO 98/11223, WO 00/27819, WO 01/55114, WO01/58899 and EP 0 769 947; those as described by M. Prewett et al inCancer Research 59 (1999) 5209-5218, by F. Yuan et al in Proc. Natl.Acad. Sci. USA, vol. 93, pp. 14765-14770, December 1996, by Z. Zhu et alin Cancer Res. 58, 1998, 3209-3214, and by J. Mordenti et al inToxicologic Pathology, vol. 27, no. 1, pp 14-21, 1999; in WO 00/37502and WO 94/10202; Angiostatin™, described by M. S. O'Reilly et al, Cell79, 1994, 315-328; and Endostatin™, described by M. S. O'Reilly et al,Cell 88, 1997, 277-285;

compounds which decrease the activity of EGF are especially compoundswhich inhibit the EGF receptor, especially the tyrosine kinase activityof the EGF receptor, and compounds binding to EGF, and are in particularthose compounds generically and specifically disclosed in WO 97/02266,EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP 0837 063, WO 98/10767, WO 97/30034, WO 97/49688, WO 97/38983 and,especially, WO 96/33980;compounds which decrease the activity of c-Src include, but are notlimited to, compounds inhibiting the c-Src protein tyrosine kinaseactivity as defined below and to SH2 interaction inhibitors such asthose disclosed in WO97/07131 and WO97/08193;compounds inhibiting the c-Src protein tyrosine kinase activity include,but are not limited to, compounds belonging to the structure classes ofpyrrolopyrimidines, especially pyrrolo[2,3-d]pyrimidines, purines,pyrazopyrimidines, especially pyrazo[3,4-d]pyrimidines,pyrazopyrimidines, especially pyrazo[3,4-d]pyrimidines andpyridopyrimidines, especially pyrido[2,3-d]pyrimidines. Preferably, theterm relates to those compounds disclosed in WO 96/10028, WO 97/28161,WO97/32879 and WO97/49706;compounds which decreases the activity of the protein kinase C areespecially those staurosporine derivatives disclosed in EP 0 296 110(pharmaceutical preparation described in WO 00/48571) which compoundsare protein kinase C inhibitors;further specific compounds that decrease protein kinase activity andwhich may also be used in combination with the compounds of the presentinvention are Imatinib (Gleevec®/Glivec®), PKC412, Iressa™ (ZD1839),PKI166, PTK787, ZD6474, GW2016, CHIR-200131, CEP-7055/CEP-5214,CP-547632, KRN-633 and SU5416;anti-angiogenic compounds having another mechanism of action thandecreasing the protein kinase activity include, but are not limited toe.g. thalidomide (THALOMID), celecoxib (Celebrex) and ZD6126.

The term “gonadorelin agonist” as used herein includes, but is notlimited to abarelix, goserelin and goserelin acetate. Goserelin isdisclosed in U.S. Pat. No. 4,100,274 and can be administered, e.g., inthe form as it is marketed, e.g. under the trademark ZOLADEX™. Abarelixcan be Formulated, e.g. as disclosed in U.S. Pat. No. 5,843,901.

The term “anti-androgens” as used herein includes, but is not limited tobicalutamide (CASODEX™), which can be Formulated, e.g. as disclosed inU.S. Pat. No. 4,636,505.

The term “bengamides” relates to bengamides and derivatives thereofhaving aniproliferative properties.

The term “bisphosphonates” as used herein includes, but is not limitedto etridonic acid, clodronic acid, tiludronic acid, pamidronic acid,alendronic acid, ibandronic acid, risedronic acid and zoledronic acid.“Etridonic acid” can be administered, e.g., in the form as it ismarketed, e.g. under the trademark DIDRONEL™. “Clodronic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark BONEFOS™. “Tiludronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark SKELID™. “Pamidronicacid” can be administered, e.g., in the form as it is marketed, e.g.under the trademark AREDIA™. “Alendronic acid” can be administered,e.g., in the form as it is marketed, e.g. under the trademark FOSAMAX™.“Ibandronic acid” can be administered, e.g., in the form as it ismarketed, e.g. under the trademark BONDRANAT™. “Risedronic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark ACTONEL™. “Zoledronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark ZOMETA™.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to trastuzumab (Herceptin™), Trastuzumab-DM1, erlotinib(Tarceva™), bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553(anti-CD40) and 2C4 Antibody.

For the treatment of acute myeloid leukemia (AML), compounds of Formula(I) (or exemplary formula thereof) can be used in combination withstandard leukemia therapies, especially in combination with therapiesused for the treatment of AML. In particular, compounds of Formula (I)(or exemplary formula thereof) can be administered in combination withe.g. farnesyltransferase inhibitors and/or other drugs useful for thetreatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16,Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.

The structure of the active agents identified by code nos., generic ortrade names may be taken from the actual edition of the standardcompendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

The above-mentioned compounds, which can be used in combination with acompound of the Formula (I) (or exemplary formula thereof), can beprepared and administered as described in the art such as in thedocuments cited above.

General Process Conditions

All process steps described here can be carried out under known reactionconditions, preferably under those specifically mentioned, in theabsence of or usually in the presence of solvents or diluents,preferably such as are inert to the reagents used and able to dissolvethese, in the absence or presence of catalysts, condensing agents orneutralising agents, for example ion exchangers, typically cationexchangers, for example in the H⁺ form, depending on the type ofreaction and/or reactants at reduced, normal, or elevated temperature,for example in the range from −100° C. to about 190° C., preferably fromabout −80° C. to about 150° C., for example at −80 to −60° C., at roomtemperature, at −20 to 40° C. or at the boiling point of the solventused, under atmospheric pressure or in a closed vessel, whereappropriate under pressure, and/or in an inert atmosphere, for exampleunder argon or nitrogen.

It should be emphasized that reactions analogous to the conversionsmentioned in this chapter may also take place at the level ofappropriate intermediates.

DETAILED DESCRIPTION OF THE PROCESS

The heteroaryl aryl ureas of the present invention may be preparedaccording to methods known in the art.

According to a general exemplary process, compounds of having thestructure of general formula (I), may be prepared by reacting aheteroaryl amine of general Formula (VIII) with an aryl isocyanate ofgeneral Formula (IX):

The reaction may for example be carried out in an aprotic solvent, suchas toluene, for example. An exemplary procedure is shown below:

A preferred embodiment is as follows:

According to a general exemplary process, compounds of having thestructure of general formula (I*), may be prepared by reacting aheteroaryl amine of general Formula (VIIIp) with an aryl isocyanate ofgeneral Formula (IXp):

The reaction may for example be carried out in an aprotic solvent, suchas toluene, for example. An exemplary procedure is shown below:

A preferred embodiment is as follows:

Additional Process Steps

In the additional process steps, carried out as desired, functionalgroups of the starting compounds which should not take part in thereaction may be present in unprotected form or may be protected forexample by one or more of the protecting groups mentioned hereinaboveunder “protecting groups”. The protecting groups are then wholly orpartly removed according to one of the methods described there.

Salts of a compound of Formula (I) (or exemplary formula thereof) with asalt-forming group may be prepared in a manner known per se. Acidaddition salts of compounds of Formula (I) (or exemplary formulathereof) may thus be obtained by treatment with an acid or with asuitable anion exchange reagent.

Salts can usually be converted to free compounds, e.g. by treating withsuitable basic agents, for example with alkali metal carbonates, alkalimetal hydrogencarbonates, or alkali metal hydroxides, typicallypotassium carbonate or sodium hydroxide.

Stereoisomeric mixtures, e.g. mixtures of diastereomers, can beseparated into their corresponding isomers in a manner known per se bymeans of suitable separation methods. Diastereomeric mixtures forexample may be separated into their individual diastereomers by means offractionated crystallization, chromatography, solvent distribution, andsimilar procedures. This separation may take place either at the levelof a starting compound or in a compound of Formula (I) (or exemplaryformula thereof) itself. Enantiomers may be separated through theformation of diastereomeric salts, for example by salt formation with anenantiomer-pure chiral acid, or by means of chromatography, for exampleby HPLC, using chromatographic substrates with chiral ligands.

A compound of the invention, where hydrogen is present, can be convertedto the respective compound wherein R³ or R^(z) is lower alkyl byreaction e.g. with a diazo lower alkyl compound, especiallydiazomethane, in an inert solvent, preferably in the presence of a noblemetal catalyst, especially in dispersed form, e.g. copper, or a noblemetal salt, e.g. copper(I)-chloride or copper(II)-sulfate. Also reactionwith lower alkylhalogenides is possible, or with other leaving groupcarrying lower alkanes, e.g. lower alkyl alcohols esterified by a strongorganic sulfonic acid, such as a lower alkanesulfonic acid (optionallysubstituted by halogen, such as fluoro), an aromatic sulfonic acid, forexample unsubstituted or substituted benzenesulfonic acid, thesubstituents preferably being selected from lower alkyl, such as methyl,halogen, such as bromo, and/or nitro, e.g. esterified by methanesulfonicacid, or p-toluene sulfonic acid. The alkylation takes place under usualconditions for alkylation of amides, especially in aqueous solutionand/or in the presence of polar solvents, typically alcohols, forexample methanol, ethanol, isopropanol, or ethylene glycol, or dipolaraprotic solvents, e.g. tetrahydrofuran, dioxane, or dimethylformamide,where applicable in the presence of acidic or basic catalysts, generallyat temperatures from about 0° C. to the boiling temperature of thecorresponding reaction mixture, preferably between 20° C. and refluxtemperature, if necessary under increased pressure, e.g. in a sealedtube, and/or under inert gas, typically nitrogen or argon.

Salts may be present in all starting compounds and transients, if thesecontain salt-forming groups. Salts may also be present during thereaction of such compounds, provided the reaction is not therebydisturbed.

At all reaction stages, isomeric mixtures that occur can be separatedinto their individual isomers, e.g. diastereomers or enantiomers, orinto any mixtures of isomers, e.g. racemates or diastereomeric mixtures.

The invention relates also to those forms of the process in which onestarts from a compound obtainable at any stage as a transient andcarries out the missing steps, or breaks off the process at any stage,or forms a starting material under the reaction conditions, or uses saidstarting material in the form of a reactive derivative or salt, orproduces a compound obtainable by means of the process according to theinvention and processes the said compound in situ. In the preferredembodiment, one starts from those starting materials which lead to thecompounds described hereinabove as preferred, particularly as especiallypreferred, primarily preferred, and/or preferred above all.

In the preferred embodiment, a compound of Formula (I) (or exemplaryformula thereof) is prepared according to or in analogy to the processesand process steps defined in the Examples.

The compounds of Formula (I) (or exemplary formula thereof), includingtheir salts, are also obtainable in the form of hydrates, or theircrystals can include for example the solvent used for crystallization(present as solvates).

EXAMPLES

The following Examples serve to illustrate the invention withoutlimiting the scope thereof.

Temperatures are measured in degrees Celsius. Unless otherwiseindicated, the reactions take place at room temperature underN_(z)-atmosphere.

The R_(f) values which indicate the ratio of the distance moved by eachsubstance to the distance moved by the eluent front are determined onsilica gel thin-layer plates (Merck, Darmstadt, Germany) by thin-layerchromatography using the respective named solvent systems.

Most respective anilines are described in WO 03/099771 or can beprepared analogously to the therein exemplified derivatives. All othersare described elsewhere.

HPLC Conditions

Gradient A: Performed on a Waters system equipped with a CTC AnalyticsHTS PAL autosampler, 515 pumps, and a 996 DAD detector operating at 210nm. Column: CC70/3 Nucleosil 100-3 C₁₈ (3μ, 70×3 mm, Macherey-Nagel,order #721791.30), temperature: 45° C., flow: 1.2 mL min⁻¹. Eluents: A:Water+0.2% H₃PO₄ (85%, (Merck 100552)+2% Me₄NOH, (10%, Merck 108123), B:Acetonitrile+20% water+0.1% H3PO₄ (85%)+1% Me₄NOH (10%). Gradient: 0% Bto 95% B within 6.6 min., then 95% B 4.4 min.

Gradient B: Linear gradient 20-100% CH₃CN (0.1% TFA) and H₂O (0.1% TFA)in 7 min+2 min 100% CH₃CN (0.1% TFA); detection at 215 nm, flow rate 1mL/min at 30° C. Column: Nucleosil 100-3 C18 (125×4.0 mm).

Gradient C: Column: (50×4.6 mm) packed with reversed-phase materialC18-Nucleosil (Interchrom UP30 DB-5QS, Optisphere 3 μM ODB). Detectionby UV absorption at 215 nm. The retention times (t_(R)) are given inminutes. Flow rate: 2 ml/min. Gradient: 20% 100% a) in b) for 14 min+5min 100% a). a): Acetonitrile+0.1% TFA; b): water+0.1% TFA.

Gradient D: Column: (50×4.6 mm) packed with reversed-phase materialC18-Nucleosil (Interchrom UP30 DB-5QS, Optisphere 3 μM ODB). Detectionby UV absorption at 215 nm. The retention times (t_(R)) are given inminutes. Flow rate: 2 ml/min. Gradient: 15% 100% a) in b) for 2.25min+1.25 min 100% a). a): Acetonitrile+0.1% TFA; b): water+0.1% TFA.

Gradient E: Column: (50×4.6 mm) packed with reversed-phase materialC18-Nucleosil (Interchrom UP30 DB-5QS, Optisphere 3 μM ODB). Detectionby UV absorption at 215 nm. The retention times (t_(R)) are given inminutes. Flow rate: 2 ml/min.Gradient: 5% 60% a) in b) for 9 min+7 min60% a). a): Acetonitrile+0.1% TFA; b): water+0.1% TFA.

Gradient F: Column: (125×4 mm) packed with Nucleosil 100-5 C18 AB.Detection by UV absorption at 215 nm. The retention times (t_(R)) aregiven in minutes. Flow rate: 1.5 ml/min. Linear gradient: 5%-100% CH₃CN(0.1% TFA) and H₂O (0.1% TFA) in 5 min, then 100% CH₃CN (0.1% TFA) for 1min.

Gradient G: Column: (125×4 mm) packed with Nucleosil 100-5 C18 AB.Detection by UV absorption at 215 nm. The retention times (t_(R)) aregiven in minutes. Flow rate: 1.5 ml/min. Linear gradient: 10%-100% CH₃CN(0.1% TFA) and H₂O (0.1% TFA) in 5 min, then 100% CH₃CN (0.1% TFA) for 1min.

Gradient H: Column: (125×4 mm) packed with Nucleosil 100-5 C18 AB.Detection by UV absorption at 215 nm. The retention times (t_(R)) aregiven in minutes. Flow rate: 1.5 ml/min. Linear gradient: 30%-100% CH₃CN(0.1% TFA) and H₂O (0.1% TFA) in 5 min, then 100% CH₃CN (0.1% TFA) for 1min.

Gradient I: Column: (250×4 mm) packed with Nucleosil 100-5 C18 AB.Detection by UV absorption at 215 nm. The retention times (t_(R)) aregiven in minutes. Flow rate: 2 ml/min. Linear gradient: 2%-100% CH₃CN(0.1% TFA) and H₂O (0.1% TFA) in 10 min, then 100% CH₃CN (0.1% TFA) for3 min.

Gradient J: Linear gradient 20-100% CH₃CN in 5 min+1.5 min 100% CH₃CN(0.1% TFA); detection at 215 nm, flow rate 1 ml/min at 30° C. Column:Nucleosil 100-3 C18 (70×4.0 mm).

Abbreviations

-   Ac=Acetyl-   AcCN=Acetonitrile-   Anal. elemental analysis (for indicated atoms, difference between    calculated and measured value ≦0.4%)-   Brine=saturated aqueous solution of sodium chloride conc.    concentrated-   d day(s)-   DCM=Dichloromethane-   DIPE diisopropyl-ether-   DIPEA=N,N-Diisopropylethylamine-   DMAP dimethylaminopyridine-   DMEU 1,3-dimethyl-2-imidazolidinone-   DMF dimethyl formamide-   DMSO=Dimethylsulfoxide-   EE=Ethyl acetate-   ESI-MS=Electro-spray ionization mass spectroscopy-   Ether diethylether-   EtOAc ethyl acetate-   EtOH=Ethanol-   Et₃N triethylamine-   Ex. Example-   h hour(s)-   HATU=O-(7-Azobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate-   HPLC=High performance liquid chromatography-   Hx=Hexanes-   L litre(s)-   Me methyl-   MeOH=Methanol-   min minute(s)-   m.p.=Melting point-   MPLC medium pressure liquid chromatography    -   Combi Flash system: normal phase SiO₂    -   Gilson system: reversed phase Nucleosil C18 (H₂O/CH₃CN+TFA),        generally product obtained as free base after neutralization        with NaHCO₃-   MS mass spectrum-   NEt₃ triethylamine-   NMP=N-methyl-pyrrolidinone-   NMR=Nuclear magnetic resonance spectroscopy-   Pd(PhCN)₂Cl₂=Bis(benzonitrile)palladium (II) chloride-   R_(f)=Retention factor (TLC)-   RT=Room temperature-   sat. saturated-   TBME=tert.-Butyl methyl ether-   TFA=Trifluoroacetic acid-   THF=Tetrahydrofuran-   TLC=Thin layer chromatography-   t_(R)=Retention time (HPLC)-   triphosgene bis(trichloromethyl) carbonate

PREPARATIONS Preparation 1 2,6-Dichloro-3-methoxyisocyanate

To a solution of 2,6-dichloro-3-methoxyaniline (0.25 g, 1.30 mmol, 1.0eq.) in dioxane (7.5 ml) is added a 20% phosgene solution in toluene(0.69 ml, 1.30 mmol, 1.0 eq.) via a hypodermic syringe. The light brownreaction mixture is stirred under nitrogen at room temperature overnight. The obtained clear solution is high vacuum evaporated using arotary evaporator at 45° C. bath temperature to afford a brown oil thatsolidifies upon standing: 400 MHz ¹H-NMR (CDCl₃) δ: 3.90 (s, 3H, OMe),6.72 (d, 1H, Ar—H4), 7.27 (d, 1H, Ar—H5).

2,6-Dichloro-3-methoxyaniline

To a solution of 2,4-dichloro-3-aminophenol hydrochloride (GLSynthesis,7.70 g, 35.9 mmol, 1.0 eq.) in acetone is added powdered potassiumhydroxide 85% (9.48 g, 143.6 mmol, 4.0 eq.) in small portions. Then,dimethyl sulfate (5.13 ml, 53.9 mmol, 1.5 eq.) is added at such a ratethat the internal temperature does not rise above 30° C. After 1 hstirring at room temperature water (50 ml) is added and stirring iscontinued for another hour. The solvent is evaporated and the residue isdistributed between ethyl acetate (150 ml) and water (100 ml). Theorganic layer is isolated, dried over Na₂SO₄ and evaporated to give ayellow oil. Kugelrohr distillation affords the desired product as acolorless oil: b.p. 150° C./0.3 mbar, HPLC: t_(R)=5.61 min (purity: 90%,gradient A), 400 MHz ¹H-NMR (CDCl₃) δ: 3.87 (s, 3H, OMe), 4.49 (br s,2H, NH₂), 6.30 (d, 1H, Ar—H4), 7.11 (d, 1H, Ar—H5).

Preparation 2: 2,6-Dichloro-3,5-dimethoxyaniline

To a solution of N-(2-chloro-3,5-dimethoxy-phenyl)-acetamide (6.72 g,25.4 mmol) in ethanol (400 ml) is added 3M KOH (134 ml). Then, thereaction mixture is refluxed for 90 h. After cooling water (270 ml) isadded dropwise with vigorous stirring. The precipitate formed isfiltered off, washed (1× EtOH/water 1:1, 50 ml, 1× water, 100 ml), andvacuum dried at 50° C. overnight. The title compound was obtained ascolorless crystals: HPLC: t_(R)=5.43 min (purity: >99%, gradient A),ESI-MS: 221.9/223.9/225.8 [MH]⁺, 400 MHz ¹H-NMR (CDCl₃) δ: 3.89 (s, 6H,2×OMe), 4.56 (br s, 2H, NH₂), 6.03 (s, 1H, Ar—H4).

N-(2-chloro-3,5-dimethoxy-phenyl)-acetamide

Sulfurylchloride (26.9 ml, 325 mmol, 1.93 eq.) is added (in 7 min) to acold (0° C.) suspension of N-(3,5-dimethoxyphenyl)-acetamide (32.9 g,169 mmol) in AcCN (500 ml), under an inert atmosphere. The resultingyellowish is allowed to stir 30 min and quenched by dropwise addition ofa saturated aqueous solution of sodium bicarbonate (250 ml). Theresulting precipitate is collected by vacuum filtration, washed withwater (300 ml) and dried to afford 20 g of the desired product (batch1). The filtrate is diluted with a saturated aqueous solution of sodiumbicarbonate (300 ml) and extracted with EE (2×300 ml). The organic phaseis washed with water and brine, dried (sodium sulphate), filtered andconcentrated. The residue is purified by silica gel columnchromatography (EE/Hx, 1:1→2:1) to provide 8.8 g of product (batch 2).Batch 1 and 2 are combined and stirred in hexane. The solid is collectedby filtration, washed with hexane and dried to afford 25.8 g of thetitle compound as a white solid. ESI-MS: 264.0/266.0 [MH]⁺.

Preparation 3: N-(3-Amino-4-methyl-phenyl)-3-trifluoromethyl-benzamide

A suspension of N-(4-methyl-3-nitro-phenyl)-3-trifluoromethyl-benzamide(9.91 g, 30.6 mmol) and 10% palladium on charcoal (990 mg) in ethanol(180 ml) is hydrogenated at atmospheric pressure and room temperature.After 2 h the reaction is complete, the catalyst is removed byfiltration through Celite, and the filtrate is evaporated to dryness.Recrystallization of the crude product from ethyl acetate/hexanesfollowed by vacuum drying at 45° C. overnight affords the title compoundas fluffy light grey needles: HPLC: t_(R)=5.38 min (purity: >99%,gradient A), ESI-MS: 295.3 [MH]⁺

N-(4-methyl-3-nitro-phenyl)-3-trifluoromethyl-benzamide

To a solution of 4-methyl-3-nitroaniline (5 g, 32.2 mmol, 1.0 eq.) andtriethylamine (5.38 ml, 38.6 mmol, 1.2 eq.) in dichloromethane (100 ml)is added a solution of 3-tri-fluoromethylbenzoyl chloride 33.8 mmol,1.05 eq.) within 30 min. The suspension formed is stirred for 1 h atroom temperature. Then, the reaction mixture is diluted withdichloromethane (800 ml) and extracted with water (100 ml), 2M aqueousNa₂CO₃ (100 ml), 2M HCl (100 ml), water (100 ml). The organic layer isdried over Na₂SO₄, evaporated to a volume of about 100 ml and dilutedwith hexanes (100 ml). The precipitate is filtered off, washed withhexanes /dichloromethane 1:1 and hexanes. Vacuum drying over night atroom temperatures gives light yellow fine needles: HPLC: t_(R)=6.72 min(purity: >99%, gradient A), ESI-MS: 325.2 [MH]⁺

Preparation 44-(4-Methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzoic acid

To a solution of ethyl4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzoate (7.23 g,21.1 mmol, 1.0 eq.) in ethanol (40 ml) is added 1M NaOH (30.6 ml, 30.6mmol, 1.4 eq.). After stirring for 2 h at room temperature a clear paleyellow solution is obtained. The mixture is evaporated to a volume of 30ml. Then, the solution is adjusted to pH 7 by addition of 1M HCl and thesolvent is stripped off. The residue is taken up three times in toluene(70 ml) and evaporated. The crude material is dissolved in ethanol/THF1:9 (150 ml), filtered, evaporated, triturated with ethyl acetate, andvacuum dried at 60° C. over night to afford a beige powder: HPLC:t_(R)=3.61 min (purity: >99%, gradient A), ESI-MS: 303.3 [MH]⁺

Ethyl 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzoate

To a solution of N-methylpiperazine (5.8 g, 57.9 mmol, 1.0 eq.) intetrahydrofuran (225 ml) containing anhydrous finely ground potassiumcarbonate (10.4 g, 75.2 mmol, 1.3 eq.) is added a solution of ethyl4-bromomethyl-3-trifluoromethylbenzoate (18.0 g, 57.9 mmol, 1.0 eq.) intetrahydrofuran with vigorous mechanical stirring within 20 min.Stirring is continued at room temperature for 20 h. The obtainedsuspension is filtered, and the filtrate is evaporated to give a brownoil. The crude product is purified by medium pressure chromatography(290 g silica gel, gradient: TBME to EtOH/TBME 1:4 within 30 min, then25% NH₃/EtOH/TBME 1:19:80 for 60 min). The fractions containing thetitle compound are pooled and evaporated to afford a yellow oil: HPLC:t_(R)=4.75 min (purity: >99%, gradient A), ESI-MS: 331.4 [MH]⁺.

Ethyl 4-bromomethyl-3-trifluoromethyl-benzoate

A mixture of ethyl 4-methyl-3-trifluoromethylbenzoate (25.19 g, 108.5mmol, 1.0 eq.), N-bromosuccinimide (19.94 g, 112.02 mmol, 1.03 eq.) andbenzoyl peroxide (0.21 g, 0.83 mmol, 0.75 mol %) is heated to reflux andilluminated by a 100 W daylight lamp for 7 h. After cooling to roomtemperature the formed succinimide is filtered off. The filtrate isevaporated to dryness giving a yellow oil. Flash chromatography(TBME/hexanes) gives a colorless oil that solidifies upon standing:HPLC: t_(R)=7.17 min (purity: 97%, gradient A), TLC: R_(f)=0.30(TBME/hexanes 1:9).

Ethyl 4-methyl-3-trifluoromethylbenzoate

A solution of commercially available 4-methyl-3-trifluoromethylbenzoicacid (24.5 g, 120 mmol) and conc. sulfuric acid (6.5 ml) in dry ethanol(245 ml) is refluxed for 23 h. After reaching room temperature thesolvent is evaporated and the residue is neutralized by addition ofsaturated aqueous NaHCO₃ solution. The mixture is extracted with ethylacetate (3×40 ml). The organic extracts are combined, dried over Na₂SO₄and evaporated to dryness to afford a pale yellow oil: HPLC: t_(R)=7.15min (purity: >96%, gradient A), ESI-MS: 233.3 [MH]⁺.

Example 13-(2,6-Dichloro-3-methoxy-phenyl)-1-methyl-1-(6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl)-urea

To a solution of 2,6-dichloro-3-methoxyphenylisocyanate (preparation 1,52.3 mg, 0.24 mmol, 1.2 eq.) in toluene (2.5 ml) is addedN-methyl-N′-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine(59.7 mg, 0.2 mmol, 1.0 eq.). The obtained suspension is stirred underargon at 110° C. for 17 h. After cooling the crude product is filteredoff and purified by flash chromatography (100% DCM to 5% MeOH in DCMwithin 35 min). Fractions containing the product are pooled andevaporated to dryness. The residue is triturated with ether (2 ml) andtreated with ultra sound until a homogeneous suspension is obtained. Theprecipitate is filtered off and vacuum dried at 60° C. over night toafford the title compound as a colorless powder: m.p. 161.5-163° C.,HPLC: t_(R)=5.07 min (purity: >99%, gradient A), ESI-MS:516.6/518.5/520.4 [MH]⁺.

N-Methyl-N′-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine

A solution of (6-chloro-pyrimidin-4-yl)-methyl-amine (1.65 g, 11.5 mmol,1.1 eq.) and commercially available 4-(4-methylpiperazin-1-yl)-aniline(2.0 g, 10.5 mmol, 1.0 eq.) in a mixture of water (4 ml) and glacialacetic acid (16 ml) is heated to 100° C. internal temperature for 16 h.After cooling the solvent is evaporated.

The residue is taken up in methanol (50 ml) and made alkaline byaddition of 25% NH₃ in water. To this silica gel (11 g) is added and thesolvent is evaporated. The silica adsorbed crude product is purified bymedium pressure liquid chromatography (A: TBME; B: MeOH—NH₃ 99:1;gradient: 5% B->25% B in 180 min). The fractions containing the productare pooled and evaporated to dryness. The residue is triturated withether. The product is filtered off, washed with ether, and vacuum driedat 50° C. over night to give the title compound as pale yellow powder:t_(R)=3.04 min (purity: 97%, gradient A), ESI-MS: 299.3 [MH]⁺.

(6-chloro-pyrimidin-4-yl)-methyl-amine

This material was prepared by a modified procedure published in theliterature (J. Appl. Chem. 1955, 5, 358): To a suspension ofcommercially available 4,6-dichloropyrimidine (20 g, 131.6 mmol, 1.0eq.) in isopropanol (60 ml) is added 33% methylamine in ethanol (40.1ml, 328.9 mmol, 2.5 eq.) at such a rate that the internal temperaturedoes not rise above 50° C. After completion of the addition the reactionmixture was stirred for 1 h at room temperature. Then, water (50 ml) isadded and the suspension formed is chilled in an ice bath to 5° C. Theprecipitated product is filtered off, washed with cold isopropanol/water2:1 (45 ml) and water. The collected material is vacuum dried over nightat 45° C. to afford the title compound as colorless powder: t_(R)=3.57min (purity: >99%, gradient A), ESI-MS: 144.3 /146.2 [MH]⁺.

Example 23-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

To a solution of 2,6-dichloro-3,5-dimethoxyaniline (preparation 2, 74mg, 0.34 mmol, 1.25 eq.) in dioxane is added 20% phosgene solution intoluene (191 μl, 0.36 mmol, 1.35 eq.) under argon. The reaction mixtureis stirred for further 6 h at room temperature under argon. Then, thesolvent is evaporated and the colorless crystalline residue is taken upin dry toluene (2.5 ml). After the addition ofN-methyl-N′-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine(see example 1, 80 mg, 0.27 mmol, 1.0 eq.) the suspension is stirred at70° C. for 36 h under argon. After cooling the precipitate is filteredoff, washed with toluene, methanol/ether 1:1, and ether to give a beigepowder. The crude product is purified by flash chromatography (1% MeOHin DCM to 16% MeOH in DCM within 30 min). The fractions containing theproduct are pooled, evaporated, and triturated with ether. Theprecipitate is filtered off, washed (1× cold methanol/ether 1:1, 1×ether), and vacuum dried at 45° C. over night to afford the titlecompound as colorless powder: m.p. 221° C. (dec.), ESI-MS:546.1/548.0/550.0 [MH]⁺.

By following the procedures of Examples 1 and 2 but using theappropriate starting materials, examples 3—may be prepared:

Example 33-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[3-(4-methyl-piperazin-1-4-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, m.p. 157-160° C., ESI-MS: 546.1/547.8/549.9 [MH]⁺.

Example 41-(2,6-Dichloro-phenyl)-3-{6-(4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, HPLC: t_(R)=3.84 min (purity: >99%, gradient B),ESI-MS: 472/474/476 [MH]⁺.

Example 51-(2,6-Dichloro-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

Beige powder, m.p. 209-212° C., TLC: R_(f)=0.36 (DCM/MeOH/25% NH₃350:50:1), ESI-MS: 472/474/476 [MH]⁺.

Example 61-(2-Chloro-6-methyl-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.41 (DCM/MeOH/25% NH₃ 350:50:1), HPLC:t_(R)=10.39 min (purity: 98%, Gradient C), ESI-MS: 452/454 [MH]⁺.

Example 71-(2-Chloro-6-methyl-phenyl)-3-(6-[3-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.29 (DCM/MeOH/25% NH₃ 350:50:1), HPLC:t_(R)=7.91 min (purity: 99%, Gradient C), ESI-MS: 452/454 [MH]⁺.

Example 81-(3-Methoxy-phenyl)-3-{6-[4-(4-methyl-Piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

Beige powder, HPLC: t_(R)=4.52 min (purity: >99%, gradient A), ESI-MS:434.4 [MH]⁺.

Example 91-(3-Methoxy-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.20 (TBME/MeOH/NH₃ 90:9:1), HPLC:t_(R)=4.67 min (purity: >99%, gradient A), ESI-MS: 434.4 [MH]⁺.

Example 101-(3,5-Dichloro-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, HPLC: t_(R)=5.62 min (purity: >99%, gradient A),ESI-MS: 472.3/474.2 [MH]⁺.

Example 111-(3,5-Dichloro-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, HPLC: t_(R)=5.71 min (purity: >99%, gradient A),ESI-MS: 472.4/474.2 [MH]⁺.

Example 121-(2,5-Dimethoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.44 (TBME/MeOH/NH3 80:18:2), HPLC:t_(R)=4.76 min (purity: 90%, gradient A), ESI-MS: 464.4 [MH]⁺.

Example 131-(2,5-Dimethoxy-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.27 (TBME/MeOH/NH₃ 80:18:2), HPLC:t_(R)=4.90 min (purity: >99%, gradient A), ESI-MS: 464.4 [MH]⁺.

Example 141-{6-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-3-(3,4,5-trimethoxy-phenyl)-urea

Colorless powder, TLC: Rf=0.30 (TBME/MeOH/NH3 80:18:2), HPLC: t_(R)=4.36min (purity: >99%, gradient A), ESI-MS: 494.5 [MH]⁺.

Example 151-{6-[3-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-3-(3,4,5-trimethoxy-phenyl)-urea

Colorless powder, HPLC: t_(R)=4.72 min (purity: >99%, gradient A),ESI-MS: 494.5 [MH]⁺.

Example 161-(2,4-Dimethoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: Rf=0.24 (TBME/MeOH/NH3 80:18:2), HPLC: t_(R)=4.60min (purity: >99%, gradient A), ESI-MS: 464.4 [MH]⁺.

Example 171-(2,4-Dimethoxy-phenyl)-3-{6-[2-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea

Colorless powder, HPLC: t_(R)=4.75 min (purity: >95%, gradient A),ESI-MS: 464.4 [MH]⁺.

Example 181-(3,5-Dimethoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: Rf=0.19 (TBME/MeOH/NH3 80:18:2), HPLC: t_(R)=4.66min (purity: >99%, gradient A), ESI-MS: 464.4 [MH]⁺.

Example 191-(3,5-Dimethoxy-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea

Colorless powder, HPLC: t_(R)=4.78 min (purity: >99%, gradient A),ESI-MS: 464.4 [MH]⁺.

Example 201-(3,5-Bis-trifluoromethyl-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, HPLC: t_(R)=5.86 min (purity: >99%, gradient A),ESI-MS: 540.4 [MH]⁺.

Example 211-(3,5-Bis-trifluoromethyl-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, HPLC: t_(R)=5.98 min (purity: >99%, gradient A),ESI-MS: 540.3 [MH]⁺.

Example 221-(3,5-Dimethyl-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.69 (TBME/MeOH/NH₃ 80:18:2), HPLC:t_(R)=4.05 min (purity: >99%, gradient A), ESI-MS: 432.4 [MH]⁺.

Example 231-(3,5-Dimethyl-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.31 (TBME/MeOH/NH₃ 90:9:1), HPLC:t_(R)=5.33 min (purity: >99%, gradient A), ESI-MS: 432.4 [MH]⁺.

Example 241-(3-Chloro-4-methoxy-phenyl)-3-(6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.17 (TBME/MeOH/NH3 80:18:2), HPLC:t_(R)=4.79 min (purity: >99%, gradient A), ESI-MS: 468.3/470.4 [MH]⁺.

Example 251-(3-Chloro-4-methoxy-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.57 (TBME/MeOH/NH₃ 90:9:1), HPLC:t_(R)=4.96 min (purity: >99%, gradient A), ESI-MS: 468.3/470.3 [MH]⁺.

Example 261-(5-Methoxy-2-methyl-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea

Light grey powder, HPLC: t_(R)=4.87 min (purity: >99%, gradient A),ESI-MS: 448.4 [MH]⁺.

Example 271-(5-Methoxy-2-methyl-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.63 (TBME/MeOH/NH₃ 80:18:2), HPLC:t_(R)=4.95 min (purity: >99%, gradient A), ESI-MS: 448.5 [MH]⁺.

Example 281-(2-Chloro-5-methoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea

Colorless powder, HPLC: t_(R)=5.35 min (purity: >99%, gradient A),ESI-MS:468.3/470.4 [MH]⁺.

Example 291-(2-Chloro-5-methoxy-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea

Colorless powder, HPLC: t_(R)=5.33 min (purity: >99%, gradient A),ESI-MS: 468.4/470.5 [MH]⁺.

Example 301-(3,4-Dimethoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea

Pale yellow powder, TLC: R_(f)=0.32 (TBME/MeOH/NH3 80:18:2), HPLC:t_(R)=5.34 min (purity: 98%, gradient A), ESI-MS: 464.4 [MH]⁺.

Example 311-(3,4-Dimethoxy-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.36 (TBME/MeOH/NH3 80:18:2), HPLC:t_(R)=4.62 min (purity: 98%, gradient A), ESI-MS: 464.4 [MH]⁺.

Example 321-(4-Fluoro-3-methoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.63 (TBME/MeOH/NH3 70:27:3), HPLC:t_(R)=4.58 min (purity: >99%, gradient A), ESI-MS: 452.4 [MH]⁺.

Example 331-(4-Fluoro-3-methoxy-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea

Pale yellow powder, TLC: R_(f)=0.31 (TBME/MeOH/NH3 80:18:2), HPLC:t_(R)=4.91 min (purity: >99%, gradient A), ESI-MS: 452.4 [MH]⁺.

Example 341-(4,5-Dimethoxy-2-methyl-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.27 (TBME/MeOH/NH3 70:27:3), HPLC:t_(R)=4.62 min (purity: >99%, gradient A), ESI-MS: 478.4 [MH]⁺.

Example 351-(4,5-Dimethoxy-2-methyl-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-

Pale yellow powder, TLC: R_(f)=0.32 (TBME/MeOH/NH3 80:18:2), HPLC:t_(R)=4.77 min (purity: >99%, gradient A), ESI-MS: 478.4 [MH]⁺.

Example 361-(2,6-Dichloro-3-methoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.30 (DCM/MeOH 80:20), HPLC: t_(R)=4.83 min(purity: >100%, gradient A), ESI-MS: 502.6/504.4/506.4 [MH]⁺.

Example 371-(2,6-Dichloro-3-methoxy-phenyl)-3-{6-[3-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea

Pale yellow powder, TLC: R_(f)=0.63 (DCM/MeOH 80:20), HPLC: t_(R)=4.84min (purity: 89%, gradient A), ESI-MS: 533.6/535.5/537.5 [MH]⁺.

Example 381-(2-Chloro-3,5-dimethoxy-phenyl)-3-(6-methylamino-pyrimidin-4-yl)-urea

Colorless powder, TLC: R_(f)=0.47 (TBME/MeOH/NH3 90:9:1), HPLC:t_(R)=5.21 min (purity: >100%, gradient A), ESI-MS: 338.3/340.4 [MH]⁺.

Example 391-(2-Chloro-3,5-dimethoxy-phenyl)-3-(6-phenylamino-pyrimidin-4-yl)-urea

Colorless powder, HPLC: t_(R)=6.60 min (purity: >99%, gradient A),ESI-MS: 400.4/402.4 [MH]⁺.

Example 401-(2-Chloro-3,5-dimethoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.52 (TBME/MeOH/NH3 80:18:2), HPLC:t_(R)=5.27 min (purity: >99%, gradient A), ESI-MS: 498.4/500.2 [MH]⁺.

Example 411-(2-Chloro-3,5-dimethoxy-2-methyl-phenyl)-3-{6-[3-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.47 (TBME/MeOH/NH3 80:18:2), HPLC:t_(R)=5.29 min (purity: >99%, gradient A), ESI-MS: 498.4/500.3 [MH]⁺.

Example 421-(2-Chloro-3,5-dimethoxy-phenyl)-3-{6-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.60 (TBME/MeOH/NH3 80:18:2), HPLC:t_(R)=5.49 min (purity: >99%, gradient A), ESI-MS: 515.5/517.4 [MH]⁺.

Example 431-(2-Chloro-3,5-dimethoxy-phenyl)-3-{6-[3-(2-dimethylamino-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.20 (TBME/MeOH 30:70), HPLC: t_(R)=5.38min (purity: >99%, gradient A), ESI-MS: 487.4/489.4 [MH]⁺.

Example 441-(2-Chloro-3,5-dimethoxy-phenyl)-3-{6-[4-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, HPLC: t_(R)=5.30 min (purity: 96%, gradient A),ESI-MS: 529.4/531.3 [MH]⁺.

Example 451-(2-Chloro-3,5-dimethoxy-phenyl)-3-{6-[3-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.40 (TBME/MeOH 75:25), HPLC: t_(R)=5.29min (purity: >99%, gradient A), ESI-MS: 529.4/531.4 [MH]⁺.

Example 463-(2,3-Dimethoxy-phenyl)-1-ethyl-1-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.57 (DCM/MeOH 85:15), HPLC: t_(R)=5.29 min(purity: 98%, gradient A), ESI-MS: 492.2 [MH]⁺.

Example 473-(3,5-Dimethoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

Pale yellow powder, TLC: R_(f)=0.38 (TBME/MeOH/NH3 80:18:2), HPLC:t_(R)=5.13 min (purity: 95%, gradient A), ESI-MS: 478.5 [MH]⁺.

Example 483-(3,5-Dimethoxy-phenyl)-1-methyl-1-{6-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.48 (TBME/MeOH/NH3 80:18:2), HPLC:t_(R)=5.21 min (purity: 95%, gradient A), ESI-MS: 478.4 [MH]⁺.

Example 493-(2-Chloro-3,5-dimethoxy-phenyl)-1-methyl-1-(6-phenylamino-pyrimidin-4-yl)-urea

Colorless powder, HPLC: t_(R)=7.38 min (purity: 96%, gradient A),ESI-MS: 414.5/416.4 [MH]⁺.

Example 503-(2-Chloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, HPLC: t_(R)=5.65 min (purity: 95%, gradient A),ESI-MS: 512.4/514.3 [MH].

Example 513-(2-Chloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.53 (TBME/MeOH/NH3 80:18:2), HPLC:t_(R)=5.63 min (purity: >99%, gradient A), ESI-MS: 512.5/514.4 [MH]⁺.

Example 523-(2-Chloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.45 (DCM/MeOH 80:20), HPLC: t_(R)=5.33 min(purity: 90%, gradient A), ESI-MS: 540.5/542.4 [MH]⁺.

Example 533-(2-Chloro-3,5-dimethoxy-phenyl)-1-{6-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea

Colorless powder, TLC: R_(f)=0.22 (TBME/MeOH 75:25), HPLC: t_(R)=5.74min (purity: >99%, gradient A), ESI-MS: 529.4/531.3 [MH]⁺.

Example 543-(2-Chloro-3,5-dimethoxy-phenyl)-1-{6-[3-(2-dimethylamino-ethoxy)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea

Colorless powder, TLC: R_(f)=0.34 (TBME/MeOH/NH3 80:18:2), HPLC:t_(R)=5.57 min (purity: >99%, gradient A), ESI-MS: 501.4/503.3 [MH]⁺.

Example 553-(2-Chloro-3,5-dimethoxy-phenyl)-1-ethyl-1-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.26 (DCM/MeOH 90:10), HPLC: t_(R)=5.69 min(purity: >100%, gradient A), ESI-MS: 526.5/528.4 [MH]⁺.

Example 563-(2-Chloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-thiophen-2-ylmethyl-urea

Colorless powder, TLC: R_(f)=0.36 (DCM/MeOH 90:10), HPLC: t_(R)=6.10 min(purity: >100%, gradient A), ESI-MS: 594.5/596.4 [MH]⁺.

Example 573-(2-Chloro-3,5-dimethoxy-phenyl)-1-[2-(4-methyl-piperazin-1-yl)-ethyl]-1-(6-phenylamino-pyrimidin-4-yl)-urea

Colorless powder, TLC: R_(f)=0.15 (TBME/MeOH 50:50), HPLC: t_(R)=5.82min (purity: >100%, gradient A), ESI-MS: 526.5/528.4 [MH]⁺.

Example 583-(2-Chloro-3,5-dimethoxy-phenyl)-1-(6-phenylamino-pyrimidin-4-yl)-1-(2-pyridin-2-yl-ethyl)-urea

Colorless powder, HPLC: t_(R)=7.30 min (purity: 95%, gradient A),ESI-MS: 505.4/507.4 [MH]⁺.

Example 593-(2,6-Dichloro-3-methoxy-phenyl)-1-ethyl-1-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

Yellow foam, TLC: R_(f)=0.26 (TBME/MeOH 40:60), HPLC: t_(R)=5.37 min(purity: 96%, gradient A), ESI-MS: 530.1/532.0/534.0 [MH]⁺.

Example 603-(2,6-Dichloro-3-methoxy-phenyl)-1-methyl-1-{6-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.15 (TBME/MeOH 60:40), HPLC: t_(R)=5.31min (purity: 97%, gradient A), ESI-MS: 516.1/518.0/520.1 [MH]⁺.

Example 613-(2,6-Dichloro-3-methoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.67 (DCM/MeOH 80:20), HPLC: t_(R)=5.11 min(purity: 91%, gradient A), ESI-MS: 544.4/546.3/548.4 [MH]⁺.

Example 623-(2,6-Dichloro-3-methoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-pyrimidin-4-yl}-urea

Beige powder, HPLC: t_(R)=5.14 min (purity: 93%, gradient A), ESI-MS:529.2/531.0/533.1 [MH]⁺.

Example 633-(2,6-Dichloro-3-methoxy-phenyl)-1-(6-methoxy-pyridin-3-ylmethyl)-1-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.56 (DCM/MeOH 80:20), HPLC: t_(R)=5.69 min(purity: >99%, gradient A), ESI-MS: 623.0/625.5/627.3 [MH]⁺.

Example 643-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-ethyl-1-{6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, TLC: R_(f)=0.44 (DCM/MeOH 85:15), HPLC: t_(R)=5.23 min(purity: >99%, gradient A), ESI-MS: 588.5/590.1/592.2 [MH]⁺.

Example 651-(2-Chloro-6-methyl-phenyl)-3-(6-isopropylamino-pyrimidin-4-4-urea

Beige powder, m.p. 233-233° C., TLC: R_(f)=0.55 (DCM/MeOH/25% NH₃350:50:1), ESI-MS: 319/321 [MH]⁺.

Example 66 (2,6-dichloro-phenyl)-carbamic acid4-{6-[3-(2,6-dichloro-phenyl)-ureido]-pyrimidin-4-ylamino}-cyclohexylester

Colorless powder, m.p. 222-224° C., ESI-MS: 582/584/586 [MH]⁺.

Example 671-(6-Isopropylamino-pyrimidin-4-yl)-3-(2,4,6-trichloro-phenyl)-urea

Colorless powder, m.p. 218-220° C., HPLC: t_(R)=9.92 min (purity: 100%,gradient C).

Example 681-(2,6-Dichloro-phenyl)-3-(6-isopropylamino-pyrimidin-4-yl)-urea

Colorless powder, m.p. 203-204° C., ESI-MS: 340/342/586 [MH]⁺.

Example 691-{6-[4-(1-Methyl-piperidin-4-ylmethoxy)-phenylamino]-pyrimidin-4-yl}-3-(2,4,6-trichloro-phenyl)-urea

Slightly yellow powder, m.p. 189-191° C., ESI-MS: 535/537/539 [MH]⁺.

Example 701-(2-Chloro-6-methyl-phenyl)-3-{6-[4-(1-methyl-piperidin-4-ylmethoxy)-phenylamino]-pyrimidin-4-yl}-urea

Slightly yellow powder, m.p. 178-180° C., ESI-MS: 481/483 [MH]⁺.

Example 711-(2,6-Dichloro-phenyl)-3-{6-[4-(1-methyl-piperidin-4-ylmethoxy)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, m.p. 183-185° C., ESI-MS: 501/503 [MH]⁺.

Example 721-(2,5-Dichloro-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, m.p. 223-225° C., ESI-MS: 472/474 [MH]⁺.

Example 731-{6-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-3-(2,4,6-trichloro-phenyl)-urea

Colorless powder, m.p. 209-211° C., ESI-MS: 506/508/510 [MH]⁺.

Example 741-{6-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-3-(2,4,5-trichloro-phenyl)-urea

Colorless powder, m.p. 252-254° C., ESI-MS: 506/508/510 [MH]⁺.

Example 751-(3,4-Dichloro-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, m.p. 260-262° C., ESI-MS: 472/474 [MH]⁺.

Example 761-(6-Amino-pyrimidin-4-yl}-3-(2,3-dichloro-phenyl)-1-[4-(4-methyl-piperazin-1-yl)-phenyl]-urea

Colorless powder, m.p. 280-282° C., ESI-MS: 472/474 [MH]⁺.

Example 771-(2,3-Dichloro-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, m.p. 279-281° C., ESI-MS: 472/474 [MH]⁺.

Example 781-(5-Chloro-2-methoxy-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

Colorless resin, TLC: R_(f) 0.41 (DCM/MeOH/25% NH₃ 350:50:1), HPLC:t_(R)=13.25 min (purity: 100%, gradient E), ESI-MS: 468/470 [MH]⁺.

Example 791-(2-Chloro-6-methyl-phenyl)-3-{6-[3-(1-methyl-piperidin-4-ylmethoxy)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, m.p. 200-204° C., ESI-MS: 481/483 [MH]⁺.

Example 801-(2,6-Dichloro-phenyl)-3-{6-[3-(1-methyl-piperidin-4-ylmethoxy)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, m.p. 198-200° C., ESI-MS: 501/503 [MH]⁺.

Example 811-{6-[3-(1-Methyl-piperidin-4-ylmethoxy)-phenylamino]-pyrimidin-4-yl}-3-(2,4,6-trichloro-phenyl)-urea

Colorless powder, m.p. 222-225° C., ESI-MS: 535/537/539 [MH]⁺.

Example 821-(2-Chloro-6-methyl-phenyl)-3-{6-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, m.p. 199-201° C., ESI-MS: 466/468 [MH]⁺.

Example 831-(2,6-Dichloro-phenyl]-3-{6-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, m.p. 199-201° C., ESI-MS: 466/468 [MH]⁺.

Example 841-{6-[4-(4-Methyl-piperazin-1-ylmethyl)-phenylamino]-pyrimidin-4-yl}-3-(2,4,6-trichloro-phenyl)-urea

Yellowish powder, m.p. 194-196° C., ESI-MS: 520/522/524 [MH]⁺.

Example 851-{6-[4-(4-Methyl-piperazin-1-carbonyl)-phenylamino]-pyrimidin-4-yl}-3-(2,4,6-trichloro-phenyl)-urea

Amorphous material, m.p. 165-175° C., TLC: R_(f)=0.61 (DCM/MeOH/25% NH₃150:50:1), HPLC: t_(R)=8.63 min (purity: 98.8%, gradient C), ESI-MS:534/536/538 [MH]⁺.

Example 861-{6-[3-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-3-(2,4,6-trichloro-phenyl)-urea

Yellowish amorphous material, m.p. 138-142° C., TLC: R_(f)=0.41(DCM/MeOH/25% NH₃ 350:50:1), HPLC: t_(R)=8.92 min (purity: 99%, gradientC), ESI-MS: 506/508/510 [MH]⁺.

Example 871-{6-[(trans)-4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexylamino]-pyrimidin-4-yl}-3-(2,4,6-trichloro-phenyl)-urea

Colorless powder, m.p. 198-199° C., ESI-MS: 570/572/574 [MH]⁺.

Example 881-[6-((trans)-4-Hydroxy-cyclohexylamino)-pyrimidin-4-yl]-3-(2,4,6-trichloro-phenyl)-urea

Colorless powder, m.p. 171-173° C., ESI-MS: 430/432/434 [MH]⁺.

Example 891-[6-(trans)-4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexylamino]-pyrimidin-4-yl]-3-(2-chloro-6-methyl-phenyl)-urea

Beige powder, m.p. 218-220° C., TLC: R_(f)=0.74 (ethyl acetate/methanol95:5), HPLC: t_(R)=13.92 min (purity: 93.9%, gradient C), ESI-MS:490/492 [MH]⁺.

Example 901-(2-Chloro-6-methyl-phenyl)-3-[6-((trans)-4-hydroxy-cyclohexylamino)-pyrimidin-4-yl]-urea

Colorless powder, m.p. 149-152° C., TLC: R_(f)=0.22 (ethylacetate/methanol 95:5), HPLC: t_(R)=7.77 min (purity: 95.2%, gradientC), ESI-MS: 376/378 [MH]⁺.

Example 911-{6-[(trans)-4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexylamino]-pyrimidin-4-yl}-3-(2,6-dichloro-phenyl)-urea

Colorless powder, m.p. 211-212° C., HPLC: t_(R)=2.63 min (purity: 97.9%,gradient D), ESI-MS: 510/512 [MH]⁺.

Example 921-(2,6-Dichloro-phenyl)-3-[6-((trans)-4-hydroxy-cyclohexylamino)-pyrimidin-4-yl]-urea

Amorphous material, TLC: R_(f)=0.28 (ethyl acetate/methanol 95:5), HPLC:t_(R)=13.54 min (purity: 100%, gradient C), ESI-MS: 396/398 [MH]⁺.

Example 931-(2-Chloro-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

Beige powder, HPLC: t_(R)=4.17 min (purity: 100%, gradient B), ESI-MS:438/440 [MH]⁺.

Example 941-(2-Bromo-phenyl)-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, HPLC: t_(R)=4.23 min (purity: 100%, gradient B),ESI-MS: 482/484 [MH]⁺.

Example 951-(6-Amino-pyrimidin-4-yl]-3-(2-chloro-phenyl)-1-[4-(3-diethylamino-propoxy)-phenyl]-urea

Colorless powder, HPLC: t_(R)=4.42 min (purity: 100%, gradient B),ESI-MS: 469/471 [MH]⁺.

Example 961-(2,6-Dichloro-phenyl)-3-1644-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea

Beige powder, HPLC: t_(R)=3.93 min (purity: 100%, gradient B), ESI-MS:503/505 [MH]⁺.

Example 971-(2-Bromo-phenyl)-3-{6-[4-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea

White powder, HPLC: t_(R)=4.29 min (purity: 100%, gradient B), ESI-MS:513/515 [MH]⁺.

Example 981-(2,6-Dichloro-phenyl)-3-1614-(3-morpholin-4-yl-propoxy)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, HPLC: t_(R)=4.05 min (purity: 100%, gradient B),ESI-MS: 517/519 [MH]⁺.

Example 991-(2-Bromo-phenyl)-3-{6-[4-(3-morpholin-4-yl-propoxy)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, HPLC: t_(R)=4.42 min (purity: 100%, gradient B),ESI-MS: 527/529 [MH]⁺.

Example 1001-(2,6-Dichloro-phenyl)-3-{6-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, HPLC: t_(R)=4.12 min (purity: 100%, gradient B),ESI-MS: 489/491 [MH]⁺.

Example 1011-(2-Bromo-phenyl)-3-{6-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, HPLC: t_(R)=4.55 min (purity: 100%, gradient B),ESI-MS: 499/501 [MH]⁺.

Example 1021-(2-Chloro-phenyl)-3-{6-[4-(3-diethylamino-propoxy)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, HPLC: t_(R)=4.58 min (purity: 100%, gradient B),ESI-MS: 469/471 [MH]⁺.

Example 1031-(2,6-Dichloro-phenyl)-3-{6-[4-(3-diethylamino-propoxy)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, HPLC: t_(R)=4.26 min (purity: 100%, gradient B),ESI-MS: 503/505 [MH]⁺.

Example 1041-(2-Bromo-phenyl)-3-{6-[4-(3-diethylamino-propoxy)-phenylamino]-pyrimidin-4-yl}-urea

Colorless powder, HPLC: t_(R)=4.62 min (purity: 100%, gradient B),ESI-MS: 513/515 [MH]⁺.

Example 1051-[6-(4-Diethylamino-phenylamino)-pyrimidin-4-yl]-3-(2,6-difluoro-phenyl)-urea

A. N-(4-Diethylamino-phenyl)-pyrimidine-4,6-diamine

A mixture of 6-chloro-pyrimidin-4-ylamine (0.65 g, 5 mmol),4-amino-N,N-diethylaniline (0.82 mL, 5 mmol), 2-propanol (5 mL) and HClconc. (0.225 mL, ˜2.5 mmol) is shaken for 36 h at 90° C. After coolingto room temperature, the reaction mixture is distributed betweenhalf-saturated K₂CO₃-solution and ethyl acetate. The precipitate thusformed is filtered off, washed with H₂O and ethyl acetate and dried invacuo to afford the title compound. Greyish solid, HPLC: t_(R)=2.37 min(gradient F), ESI-MS: 258.3 [MH]⁺.

B.1-[6-(4-Diethylamino-phenylamino)-pyrimidin-4-yl]-3-(2,6-difluoro-phenyl)-urea

A mixture of N-(4-diethylamino-phenyl)-pyrimidine-4,6-diamine (257.4 mg,1 mmol), 2,6-difluorophenyl isocyanate (170.6 mg, 1.1 mmol) in drydioxane (4 mL) is shaken for 1.5 h at 80° C. After evaporation of thesolvent in vacuo, the residue is distributed between CH₂Cl₂ andhalf-saturated K₂CO₃ solution. The organic layer is dried over Na₂SO₄,evaporated, and the residue purified by flash chromatography(CH₂Cl₂/CH₃OH). The combined pure fractions are evaporated, the residuetriturated with CH₂Cl₂ and the solid filtered off and dried in vacuo toafford the title compound.

White solid, HPLC: t_(R)=3.35 min (purity:100%, gradient F), ESI-MS:413.4 [MH]⁺.

Example 1061-(2,6-Difluoro-phenyl)-3-[6-(3-dimethylamino-phenylamino)-pyrimidin-4-yl]-urea

A. N-(3-Dimethylamino-phenyl)-pyrimidine-4,6-diamine

A mixture of N,N-dimethyl-m-phenylenediamine (1.36 g, 10 mmol),6-chloro-pyrimidin-4-ylamine (1.30 g, 10 mmol), 2-propanol (10 mL) andHCl conc. (0.45 mL, ˜5 mmol) is shaken for 16 h at 90° C. After coolingto room temperature, the reaction mixture is distributed betweenhalf-concentrated Na₂CO₃ solution and ethyl acetate. The organic layeris dried over Na₂SO₄, evaporated, and the residue purified by flashchromatography (ethyl acetate /CH₃OH). The combined pure fractions areevaporated to afford the title compound.

Beige solid, HPLC: t_(R)=1.53 min (gradient F), ESI-MS: 230.3 [MH]⁺.

B.1-(2,6-Difluoro-phenyl)-3-[6-(3-dimethylamino-phenylamino)-pyrimidin-4-yl]-urea

A mixture of N-(3-dimethylamino-phenyl)-pyrimidine-4,6-diamine (458.6mg, 2 mmol), 2,6-difluorophenyl isocyanate (341.2 mg, 2.2 mmol) in drydioxane (5 mL) is shaken for 2.5 h at 80° C. After cooling down, thereaction mixture is treated with ethyl acetate. The precipitate isfiltered off and dried in vacuo to afford the title compound.

White solid, HPLC: t_(R)=3.39 min (purity: 100%, gradient F), ESI-MS:385.4 [MH]⁺.

Example 1071-(2,6-Dichloro-phenyl)-3-[6-(4-diethylamino-phenylamino)-pyrimidin-4-yl]-urea

The title compound is prepared analogously as described in Example 105Afrom N-(4-diethylamino-phenyl)-pyrimidine-4,6-diamine and2,6-dichlorophenyl isocyanate.

White solid, HPLC: t_(R)=3.61 min (purity: 100%, gradient F), ESI-MS:445.3/447.3 [MH]⁺.

Example 1081-(2,6-Dichloro-phenyl)-3-[6-(4-morpholin-4-yl-phenylamino)-pyrimidin-4-yl]-urea

A. N-(4-Morpholin-4-yl-phenyl)-pyrimidine-4,6-diamine

The title compound is prepared analogously as described in Example 105Afrom 6-chloro-pyrimidin-4-ylamine and 4-morpholinoaniline. Thesemi-solid reaction mixture received after cooling to room temperatureis dissolved in warm methanol, basified with conc. aqueous ammoniasolution and the mixture concentrated to half of its volume. Theprecipitate obtained after addition of H₂O is filtered off, washed withH₂O and dried in vacuo to afford the title compound. Faintly violetsolid, ESI-MS: 272.3 [MH]⁺.

B.1-(2,6-Dichloro-Phenyl)-3-[6-(4-morpholin-4-yl-phenylamino)-pyrimidin-4-yl]-urea

The title compound is prepared analogously as described in Example 105Bfrom N-(4-morpholin-4-yl-phenyl)-pyrimidine-4,6-diamine and2,6-dichlorophenyl isocyanate.

Faintly violet solid, HPLC: t_(R)=3.74 min (purity: 100%, gradient F),ESI-MS: 459.3/461.3 [MH]⁺.

Example 1091-(2,6-Difluoro-phenyl)-3-[6-(4-morpholin-4-yl-phenylamino)-pyrimidin-4-yl]-urea

The title compound is prepared analogously as described in Example 105Bfrom N-(4-morpholin-4-yl-phenyl)-pyrimidine-4,6-diamine and2,6-difluorophenyl isocyanate.

Slightly pink solid, HPLC: t_(R)=3.53 min (purity: 100%, gradient F),ESI-MS: 427.4 [MH]⁺.

Example 1103-(2,6-Dichloro-phenyl)-1-[6-(4-diethylamino-phenylamino)-pyrimidin-4-yl]-1-methyl-urea

A. N-(4-Diethylamino-phenyl)-N′-methyl-pyrimidine-4,6-diamine

The title compound is prepared analogously as described in Example 105Afrom (6-chloro-pyrimidin-4-yl)-methyl-amine and4-amino-N,N-diethylaniline. The ethyl acetate layer is dried over Na₂SO₄and evaporated in vacuo. The residue is suspended in CH₂Cl₂, filteredoff and dried to afford the title compound.

White solid, HPLC: t_(R)=2.48 min (gradient F), ESI-MS: 272.3 [MH]⁺.

B.3-(2,6-Dichloro-phenyl)-1-[6-(4-diethylamino-phenylamino)-pyrimidin-4-yl]-1-methyl-urea

The title compound is prepared analogously as described in Example 105Bfrom N-(4-diethylamino-phenyl)-N′-methyl-pyrimidine-4,6-diamine and2,6-dichlorophenyl isocyanate.

White solid, HPLC: t_(R)=2.46 min (purity: 95.6%, gradient H), ESI-MS:459.2/461.2 [MH]⁺.

Example 1113-(2,6-Dichloro-phenyl)-1-{6-[4-(1-hydroxy-1-methyl-ethyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea

A. 1-[4-(6-Methylamino-pyrimidin-4-ylamino)-phenyl]ethanone

A mixture of (6-chloro-pyrimidin-4-yl)-methylamine (5.76 g, 40.1 mmol),4-amino-acetophenone (5.40 g, 40 mmol), 2-propanol (40 mL) and conc. HCl(1.8 mL, ˜20 mmol) is stirred for 40 h at 90° C. Conc. HCl (0.9 mL, ˜10mmol) is added and stirring is continued for 56 h. After addition ofCH₃OH the reaction mixture is basified with conc. aqueous ammoniasolution. H₂O is added and the precipitate is filtered off, washed withH₂O and dried in vacuo to afford the title compound. Yellow solid,ESI-MS: 243.4 [MH]⁺.

B.1-[6-(4-Acetyl-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-phenyl)-1-methyl-urea

A mixture of 1-[4-(6-methylamino-pyrimidin-4-ylamino)-phenyl]-ethanone(3.77 g, 15.56 mmol), 2,6-dichlorophenyl isocyanate (3.22 g, 17.12 mmol)in dry dioxane (30 mL) is shaken for 16 h at 80° C. After evaporation ofthe solvent in vacuo, the residue is distributed between ethyl acetateand half-saturated K₂CO₃ solution. The precipitate is filtered off andwashed with H₂O and ethyl acetate. The solid residue is suspended inmethanol, heated to reflux for several h and the hot yellow suspensionfiltered. This procedure is repeated once. The residue obtained afterthe second filtration is washed with CH₃OH and dried in vacuo to affordthe title compound.

Yellowish solid, HPLC: t_(R)=4.81 min (gradient G), ESI-MS: 430.3/432.3[MH]⁺.

C.3-(2,6-Dichloro-phenyl)-1-{6-[4-(1-hydroxy-1-methyl-ethyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea

To a freshly prepared solution of methylmagnesium iodide in diethylether (8 mL, ˜7 mmol) is added1-[6-(4-acetyl-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-phenyl)-1-methyl-urea(0.5 g, 1.16 mmol) in several portions. After stirring for 5 h, THF (4mL) is added. After 16 h the reaction is quenched by the addition of H₂Oand CH₃OH and evaporated in vacuo. The residue is co-evaporated twicewith toluene and purified by flash chromatography (CH₂Cl₂/CH₃OH). Thecombined pure fractions are evaporated to afford the title compound.

White solid, HPLC: t_(R)=4.39 min (purity: 100%, gradient G), ESI-MS:446.4/448.4 [MH]⁺.

Example 1121-(2,6-Dichloro-phenyl)-3-[6-(6-methoxy-pyridin-3-ylamino)-pyrimidin-4-yl]-urea

A. N-(6-Methoxy-pyridin-3-yl)-pyrimidine-4,6-diamine

A mixture of 6-chloro-pyrimidin-4-ylamine (0.65 g, 5 mmol),5-amino-2-methoxypyridine (0.62 g, 5 mmol) and 2-propanol (5 mL) isshaken for 36 h at 90° C. After cooling to room temperature, thereaction mixture is distributed between half-saturated Na₂CO₃-solutionand ethyl acetate. The organic layer is dried over Na₂SO₄ andevaporated. The solid residue is washed consecutively with CH₃OH, ethylacetate and CH₂Cl₂ and dried in vacuo.

Pinkish solid, HPLC: t_(R)=2.68 min (gradient F), ESI-MS: 218.3 [MH]⁺.

B.1-(2,6-Dichloro-phenyl)-3-[6-(6-methoxy-pyridin-3-ylamino)-pyrimidin-4-yl]-urea

The title compound is prepared analogously as described in Example 105Bfrom N-(6-methoxy-pyridin-3-yl)-pyrimidine-4,6-diamine and2,6-dichlorophenyl isocyanate.

Slightly beige solid, HPLC: t_(R)=4.01 min (purity: 100%, gradient F),ESI-MS: 405.2/407.2 [MH]⁺.

Example 1133-(2,6-Dichloro-phenyl)-1-methyl-1-[6-(3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-urea

A. (6-Chloro-pyrimidin-4-yl)-(3-trifluoromethyl-phenyl)-amine

A stirred mixture of 4,6-dichloropyrimidine (18.6 g, 125 mmol),3-aminobenzotrifluoride (16.5 mL, 133 mmol), acetone (60 mL) and H₂O (90mL) is kept at reflux for 3 h. Acetone is removed in vacuo, theremaining aqueous layer is basified with conc. aqueous ammonia solutionand extracted with ethyl acetate. The organic extract is dried overNa₂SO₄ and evaporated. The residue is suspended in a small amount ofacetone, filtered and the filter cake dried in vacuo to afford the titlecompound.

White solid, HPLC: t_(R)=4.82 min (gradient G), ESI-MS: 274.2/276.1[MH]⁺.

B. N-Methyl-N′-(3-trifluoromethyl-phenyl)-pyrimidine-4,6-diamine

A solution of methylamine in ethanol (32 mL, 256 mmol) is added to(6-chloro-pyrimidin-4-yl)-(3-trifluoromethyl-phenyl)-amine (3.49 g, 12.8mmol) and the mixture is stirred for 5 h at 100° C. in a pressurebottle. The reaction mixture is concentrated in vacuo, the residuediluted with CH₃OH and basified using conc. aqueous ammonia solution.The product is filtered off, washed with H₂O and CH₃OH and dried invacuo.

Greyish solid, HPLC: t_(R)=3.51 min (gradient G), ESI-MS: 269.2 [MH]⁺.

C.3-(2,6-Dichloro-phenyl)-1-methyl-1-[6-(3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-urea

A mixture ofN-methyl-N′-(3-trifluoromethyl-phenyl)-pyrimidine-4,6-diamine (536.5 mg,2 mmol), 2,6-dichlorophenyl isocyanate (413.6 mg, 2.2 mmol) in drydioxane (5 mL) is shaken for 1 h at 80° C. After evaporation of thesolvent in vacuo, the residue is distributed between ethyl acetate andhalf-saturated K₂CO₃ solution. The organic layer is dried over Na₂SO₄,evaporated, and the residue recrystallized from CH₂Cl₂/CH₃OH. The solidresidue is dried in vacuo to afford the title compound.

White solid, HPLC: t_(R)=5.08 min (purity: 100%, gradient H), ESI-MS:456.3/458.3 [MH]⁺.

Example 1141-[6-(3-Cyano-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-phenyl)-1-methyl-urea

A. 3-(6-Methylamino-pyrimidin-4-ylamino)-benzonitrile

A mixture of (6-chloro-pyrimidin-4-yl)-methylamine (1.44 g, 10 mmol),3-amino-benzonitrile. (1.18 g, 10 mmol), 2-propanol (10 mL) and conc.HCl (0.45 mL, ˜5 mmol) is stirred for 36 h at 90° C. After cooling toroom temperature, CH₃OH is added and the reaction mixture is basifiedwith conc. aqueous ammonia solution. The precipitate which forms uponaddition of H₂O is filtered off, washed with H₂O and dried in vacuo toafford the title compound.

Beige solid, HPLC: t_(R)=2.67 min (gradient G), ESI-MS: 226.2 [MH]⁺.

B.1-[6-(3-Cyano-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-phenyl)-1-methyl-urea

A mixture of 3-(6-methylamino-pyrimidin-4-ylamino)-benzonitrile (450.5mg, 2 mmol), 2,6-dichlorophenyl isocyanate (413.6 mg, 2.2 mmol) in drydioxane (5 mL) is shaken for 1.5 h at 80° C. and then evaporated invacuo. The residue is suspended in half-concentrated aqueous K₂CO₃solution, filtered off, washed with H₂O and acetone and dried in vacuoto afford the title compound.

Beige solid, HPLC: t_(R)=4.34 min (purity: 100%, gradient H), ESI-MS:413.3/415.3 [MH]⁺.

Example 1151-(2,6-Dichloro-phenyl)-3-[6-(4-fluoro-phenylamino)-pyrimidin-4-yl]-urea

A. N-(4-Fluoro-phenyl)-pyrimidine-4,6-diamine

The title compound is prepared analogously as described in Example 114Afrom 6-chloro-pyrimidin-4-ylamine and 4-fluoroaniline.

Brownish solid, HPLC: t_(R)=3.09 min (gradient F), ESI-MS: 205.2 [MH]⁺.

B.1-(2,6-Dichloro-phenyl)-346-(4-fluoro-phenylamino)-pyrimidin-4-yl]-urea

A suspension of N-(4-fluoro-phenyl)-pyrimidine-4,6-diamine (408.4 mg, 2mmol), 2,6-dichlorophenyl isocyanate (413.6 mg, 2.2 mmol) in dry dioxane(5 mL) is shaken for 14 h at 80° C. After cooling to 5° C. thesuspension is filtered, the residue washed with half-saturated K₂CO₃solution, H₂O and acetone and dried in vacuo.

Greyish solid, HPLC: t_(R)=4.11 min (purity: 100%, gradient G), ESI-MS:392.3/394.3 [MH]⁺.

Example 1161-[6-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3-(4-methoxy-phenyl)-1-methyl-urea

A mixture of N-(4-fluoro-phenyl)-N′-methyl-pyrimidine-4,6-diamine (2.18g, 10 mmol), 4-methoxyphenyl isocyanate (1.29 mL, 10 mmol) anddibutyltin diacetate (0.54 mL, 2 mmol) in dry dioxane (20 mL) is shakenfor 6 h at 100° C. After addition of a second portion of 4-methoxyphenylisocyanate (0.9 mL, 7 mmol) stirring is continued at 100° C. for 9 h.The reaction mixture is treated with ethyl acetate and half-saturatedNa₂CO₃ solution. The organic layer is filtered, dried over Na₂SO₄,evaporated, and the residue purified by flash chromatography(hexane/ethyl acetate). The combined pure fractions are evaporated, theresidue is suspended in hot CH₃OH and the hot mixture filtered. Thisprocedure is repeated several times. The solid thus obtained is dried invacuo to afford the title compound.

White powder, HPLC: t_(R)=4.54 min (purity: 100%, gradient G), ESI-MS:368.3 [MH]⁺.

Example 1173-(2,6-Dichloro-phenyl)-1-methyl-1-(6-(4-morpholin-4-yl-phenylamino)-pyrimidin-4-yl]-urea

A. N-Methyl-N′-(4-morpholin-4-yl-phenyl)-pyrimidine-4,6-diamine

The title compound is prepared analogously as described in Example 114Afrom (6-chloro-pyrimidin-4-yl)-methylamine and 4-morpholinoaniline.

Slightly violet solid, HPLC: t_(R)=1.37 min (gradient G), ESI-MS: 286.3[MH]⁺.

B.3-(2,6-Dichloro-phenyl)-1-methyl-1-[6-(4-morpholin-4-yl-phenylamino)-pyrimidin-4-yl]-urea

A mixture ofN-methyl-N′-(4-morpholin-4-yl-phenyl)-pyrimidine-4,6-diamine (428.0 mg,1.5 mmol), 2,6-dichlorophenyl isocyanate (310.2 mg, 1.65 mmol) in drydioxane (5 mL) is shaken for 1.5 h at 80° C. After evaporation of thesolvent in vacuo, the residue is purified by flash chromatography(CH₂Cl₂/CH₃OH). The combined pure fractions are evaporated, the residuetriturated with CH₂Cl₂ and the solid filtered off and dried in vacuo toafford the title compound.

White solid, HPLC: t_(R)=2.79 min (purity: 100%, gradient H), ESI-MS:473.3/475.3 [MH]⁺.

Example 1183-(2,6-Dichloro-phenyl)-1-[6-(2,4-difluoro-phenylamino)-pyrimidin-4-yl]-1-methyl-urea

A. N-(2,4-Difluoro-phenyl)-N′-methyl-pyrimidine-4,6-diamine

The title compound is prepared analogously as described in Example 114Afrom (6-chloro-pyrimidin-4-yl)-methylamine and 2,4-difluoroaniline.

Pinkish solid, HPLC: t_(R)=3.21 min (gradient F), ESI-MS: 237.2 [MH]⁺.

B.3-(2,6-Dichloro-phenyl)-1-[6-(2,4-difluoro-phenylamino)-pyrimidin-4-yl]-1-methyl-urea

The title compound is prepared analogously as described in Example 105Bfrom N-(2,4-difluoro-phenyl)-N′-methyl-pyrimidine-4,6-diamine and2,6-dichlorophenyl isocyanate.

White solid, HPLC: t_(R)=4.41 min (purity: 100%, gradient H), ESI-MS:424.2/426.2 [MH]⁺.

Example 1191-(2,6-Dichloro-phenyl)-346-(3-dimethylamino-phenylamino)-pyrimidin-4-yl]-urea

The title compound is prepared analogously as described in Example 105Bfrom N-(3-dimethylamino-phenyl)-pyrimidine-4,6-diamine and2,6-dichlorophenyl isocyanate using ethyl acetate instead of CH₂Cl₂ forthe work-up procedure.

White solid, HPLC: t_(R)=3.61 min (purity: 100%, gradient F), ESI-MS:417.3/419.2 [MH]⁺.

Example 1203-(2,6-Dichloro-phenyl)-1-[6-(3-dimethylamino-phenylamino)-pyrimidin-4-yl]-1

A. N-(3-Dimethylamino-phenyl)-N′-methyl-pyrimidine-4,6-diamine

The title compound is prepared analogously as described in Example 105Afrom (6-chloro-pyrimidin-4-yl)-methylamine andN,N-dimethyl-m-phenylenediamine. The crude product obtained afterevaporation of the ethyl acetate layer is purified by flashchromatography (CH₂Cl₂/CH₃OH).

Beige solid, HPLC: t_(R)=2.45 min (gradient F), ESI-MS: 244.3 [MH]⁺.

B.3-(2,6-Dichloro-phenyl)-1-[6-(3-dimethylamino-phenylamino)-pyrimidin-4-yl]-1-methyl-urea

A mixture of N-(3-dimethylamino-phenyl)-N′-methyl-pyrimidine-4,6-diamine(243.3 mg, 1 mmol), 2,6-dichlorophenyl isocyanate (188 mg, 1 mmol) indry dimethylformamide (2.5 mL) is shaken for 14 h at 90° C. Twoadditional portions (188 mg, 1 mmol each) of 2,6-dichlorophenylisocyanate are added after 14 h and 26 h. After 38 h the reactionmixture is evaporated in vacuo and the residue is distributed betweenethyl acetate and half-saturated K₂CO₃ solution. The organic layer isdried over Na₂SO₄, evaporated, and the residue purified by flashchromatography (hexane/ethyl acetate). The combined pure fractions areevaporated, the residue triturated with CH₂Cl₂ and the solid filteredoff and dried in vacuo to afford the title compound.

White solid, HPLC: t_(R)=3.79 min (purity: 100%, gradient G), ESI-MS:431.1/433.1 [MH]⁺.

Example 1211-[6-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-1-methyl-3-(3-trifluoro-methyl-phenyl)-urea

A mixture of N-(4-fluoro-phenyl)-N′-methyl-pyrimidine-4,6-diamine (218.2mg, 1 mmol), 3-trifluoromethyl)phenyl isocyanate (165.20 L, 1.2 mmol)and dibutyltin diacetate (53.7 □L, 0.2 mmol) in dry dioxane (2.5 mL) isshaken for 14 h at 100° C. Two additional portions (82.6 □L, 0.6 mmoleach) of 3-trifluoromethyl)phenyl isocyanate are added after 14 h and 20h. After 26 h the reaction mixture is distributed between ethyl acetateand half-saturated Na₂CO₃ solution. The organic layer is dried overNa₂SO₄, evaporated, and the residue triturated with CH₂Cl₂. The solid isfiltered off and the filtrate purified by flash chromatography (hexane/ethyl acetate). The combined pure fractions are evaporated, the residuerecrystallized from CH₃OH/CH₂Cl₂ to afford the title compound.

White solid, HPLC: t_(R)=5.31 min (purity: 100%, gradient G), ESI-MS:406.3 [MH]⁺.

Example 1223-(3-Chloro-phenyl)-1-[6-(4-fluoro-phenylamino)-pyrimidin-4-yl]-1-methyl-urea

The title compound is prepared analogously as described in Example 121from N-(4-fluoro-phenyl)-N′-methyl-pyrimidine-4,6-diamine and3-chlorophenyl isocyanate.

White solid, HPLC: t_(R)=5.25 min ((purity: 100%, gradient G), ESI-MS:372.2 [MH]⁺.

Example 1233-(2,6-Dichloro-phenyl)-1-[6-(4-fluoro-phenylamino)-pyrimidin-4-yl]-1-methyl-urea

A mixture of N-(4-fluoro-phenyl)-N′-methyl-pyrimidine-4,6-diamine (218.2mg, 1 mmol), 2,6-dichlorophenyl isocyanate (188 mg, 1 mmol) andtriethylamine (1.11 mL, 8 mmol) in dry dimethylformamide (2.5 mL) isshaken for 14 h at 90° C. The reaction mixture is evaporated in vacuoand the residue is distributed between ethyl acetate and half-saturatedNa₂CO₃ solution. The organic layer is dried over Na₂SO₄, evaporated, andthe residue purified by flash chromatography (CH₂Cl₂/CH₃OH). Thecombined pure fractions are evaporated, the residue triturated withCH₂Cl₂ and the solid filtered off and dried in vacuo to afford the titlecompound.

White solid, HPLC: t_(R)=4.33 min (purity: 100%, gradient H), ESI-MS:406.1/408.1 [MH]⁺.

Example 1241-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-phenyl)-1-methyl-urea

A. N-(3-Chloro-phenyl)-N′-methyl-pyrimidine-4,6-diamine

The title compound is prepared analogously as described in Example 105Afrom (6-chloro-pyrimidin-4-yl)-methyl-amine and 3-chloroaniline. Theethyl acetate layer is dried over Na₂SO₄ and evaporated. The solidresidue is suspended in CH₂Cl₂, filtered off and dried in vacuo toafford the title compound.

White solid, HPLC: t_(R)=3.23 min (gradient G), ESI-MS: 235.2 [MH]⁺.

B.1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-phenyl)-1-methyl-urea

The title compound is prepared analogously as described in Example 105Bfrom N-(3-chloro-phenyl)-N′-methyl-pyrimidine-4,6-diamine and2,6-dichloroaniline. The oily residue received after evaporation of theCH₂Cl₂ layer is triturated with CH₂Cl₂ and the crystals thus obtainedwere filtered off and dried in vacuo to afford the title compound.

White solid, HPLC: t_(R)=4.97 min (purity: 100%, gradient H), ESI-MS:422.3/424.3 [MH]⁺.

Example 1251-(2-Chloro-phenyl)-3-{6-[4-(3-morpholin-4-yl-propoxy)-phenylamino]-pyrimidin-4-yl}-ureabis-hydrochloride salt

A. 1-(2-Chloro-phenyl)-3-(6-chloro-pyrimidin-4-yl)-urea

A solution of 6-chloro-pyrimidin-4-ylamine (997 mg, 7.7 mmol) and2-chlorophenyl isocyanate (0.46 mL, 3.85 mmol) in THF (20 mL) isrefluxed for 4 h. A further amount of 2-chlorophenyl isocyanate (0.46mL, 3.85 mmol) is added and the reaction mixture is refluxed for 28 h.The reaction mixture is cooled to RT, the precipitate is filtered toafford the title compound (1.9 g, 86%).

White powder. HPLC: t_(R)=8.01 min (gradient I), ESI-MS: 281.1/283.1[M−H]⁺

B1-(2-Chloro-phenyl)-3-{6-[4-(3-morpholin-4-yl-propoxy)-phenylamino]-pyrimidin-4-yl}-urea

A solution of 1-(2-chloro-phenyl)-3-(6-chloro-pyrimidin-4-yl)-urea (99mg, 0.35 mmol), 4-(3-morpholin-4-yl-propoxy)-phenylamine [Chabrier etal. Bull. Soc. Chim. Fr. 1955; 1353] (83 mg, 0.35 mmol), andconcentrated HCl (0.1 ml, 1.4 mmol) in ethanol (5 ml) was refluxed for32 h. The reaction mixture is cooled to RT, and diluted with water. Theacidic solution is washed with ethyl acetate, basified with aqueousammoniac, and extracted with DCM. The combined organic phases are driedover sodium sulfate, evaporated in vacuo, the residue is crystallizedfrom water/methanol/1 N HCl to afford the title compound.

Brownish crystalline powder. HPLC: t_(R)=5.92 min (gradient I), ESI-MS:483 [MH]⁺

Example 1261-(2-Chloro-phenyl)-3-{6-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea

The title compound is prepared analogously as described in Example 125Busing 4-(2-diethylamino-ethoxy)-phenylamine, crystallization from DCMafford the title compound.

White powder. HPLC: t_(R)=6.03 min (gradient I), ESI-MS: 455 [MH]⁺

Example 1271-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(2,6-dimethyl-phenyl)-1-methyl-urea

A solution of N-(3-chloro-phenyl)-N′-methyl-pyrimidine-4,6-diamine(Example 124A, 94 mg, 0.4 mmol) and 2,6-dimethylphenyl isocyanate (74mg, 0.52 mmol) in diglyme was stirred at 80° C. for 18 h. The solvent isevaporated in vacuo, and the residue is purified by column flashchromatography on silica gel (ethyl acetate/hexane 1:2) to afford titlecompound (29 mg, 19%).

White powder. HPLC: t_(R)=9.60 min (gradient I), ESI-MS: 382.3 [MH]⁺

Example 1283-(2-Chloro-phenyl)-1-[6-(3-chloro-phenylamino)-pyrimidin-4-yl]-urea

A. N-(3-Chloro-phenyl)-pyrimidine-4,6-diamine

The title compound is prepared analogously as described in Example 105Afrom 6-chloro-pyrimidin-4-ylamine and 3-chloroaniline.

White powder. m.p. 171-172° C., HPLC: t_(R)=5.11 min (gradient I),ESI-MS: 221 [MH]⁺

B. 3-(2-Chloro-phenyl)-1-[6-(3-chloro-phenylamino)-pyrimidin-4-yl]-urea

A solution of N-(3-chloro-phenyl)-pyrimidine-4,6-diamine (110 mg, 0.5mmol) and 2-chlorophenyl isocyanate (60 μL, 0.5 mmol) in diglyme (1.5mL) is stirred at 80° C. for 18 h. The precipitate which formed overtime is filtered and washed with hexane/ethyl acetate to afford the puretitle compound (98 mg, 52%).

White powder. HPLC: t_(R)=8.95 min (gradient I), ESI-MS: 374.1/376.1[MH]⁺

Example 1291-(2-Bromo-Phenyl)-3-[6-(3-chloro-phenylamino)-pyrimidin-4-yl]-urea

The title compound is prepared analogously as described in Example 128using 2-bromophenyl isocyanate.

White powder. HPLC: t_(R)=9.03 min (gradient I), ESI-MS: 418.0/420.0[MH]⁺

Example 1301-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(2-fluoro-phenyl)-urea

The title compound is prepared analogously as described in Example 128using 2-fluorophenyl isocyanate.

White powder. HPLC: t_(R)=8.24 min (gradient I), ESI-MS: 258.2 [MH]⁺

Example 1311-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(3-methoxy-phenyl)-urea

The title compound is prepared analogously as described in Example 128using 3-methoxy-phenyl isocyanate.

White powder. HPLC: t_(R)=7.90 min (gradient I), ESI-MS: 370.2 [MH]⁺

Example 1321-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(2,5-dimethoxy-phenyl)-urea

The title compound is prepared analogously as described in Example 127from N-(3-chloro-phenyl)-pyrimidine-4,6-diamine and 2,5-dimethoxyphenylisocyanate.

White powder. HPLC: t_(R)=8.18 min (gradient I), ESI-MS: 400.2 [MH]⁺

Example 1331-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(2-trifluoromethyl-phenyl)-urea

The title compound is prepared analogously as described in Example 128using 3-trifluoromethylphenyl isocyanate.

White powder. HPLC: t_(R)=8.94 min (gradient I), ESI-MS: 408.1 [MH]⁺

Example 1341-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(5-methoxy-2-methyl-phenyl)-urea

The title compound is prepared analogously as described in Example 2from 5-methoxy-2-methylaniline andN-(3-chloro-phenyl)-pyrimidine-4,6-diamine.

White powder. HPLC: t_(R)=8.38 min (gradient I), ESI-MS: 384.2 [MH]⁺

Example 1351-(3-Chloro-phenyl)-3-[6-(3-chloro-phenylamino)-pyrimidin-4-yl]-urea

The title compound is prepared analogously as described in Example 128using 3-chlorophenyl isocyanate.

White powder. HPLC: t_(R)=8.75 min (gradient I), ESI-MS: 374.1/376.1[MH]⁺

Example 1361-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(3,4,5-trimethoxy-phenyl)-urea

The title compound is prepared analogously as described in Example 127from N-(3-chloro-phenyl)-pyrimidine-4,6-diamine and3,4,5-trimethoxyphenyl isocyanate.

White powder. HPLC: t_(R)=7.60 min (gradient I), ESI-MS: 430.2 [MH]⁺

Example 1371-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-phenyl)-urea

The title compound is prepared analogously as described in Example 127from N-(3-chloro-phenyl)-pyrimidine-4,6-diamine and 2,6-dichlorophenylisocyanate.

White powder. HPLC: t_(R)=8.30 min (gradient I), ESI-MS: 410 [MH]⁺

Example 1381-(4-Chloro-phenyl)-3-[6-(3-chloro-phenylamino)-pyrimidin-4-yl]-urea

The title compound is prepared analogously as described in Example 128using 4-chlorophenyl isocyanate.

White powder. HPLC: t_(R)=8.63 min (gradient I), ESI-MS: 374.1/376.1[MH]⁺

Example 1391-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(3,5-dimethoxy-phenyl)-urea

The title compound is prepared analogously as described in Example 128using 3,5-dimethoxyphenyl isocyanate.

White powder. HPLC: t_(R)=8.06 min (gradient I), ESI-MS: 400.2 [MH]⁺

Example 1401-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-(2,6-dimethyl-phenyl)-urea

The title compound is prepared analogously as described in Example 127from N-(3-chloro-phenyl)-pyrimidine-4,6-diamine and 2,6-dimethylphenylisocyanate.

White powder. HPLC: t_(R)=7.97 min (gradient I), ESI-MS: 368.2 [MH]⁺

Example 141 1-[6-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-phenyl-urea

The title compound is prepared analogously as described in Example 128using phenyl isocyanate.

White powder. HPLC: t_(R)=7.83 min (gradient I), ESI-MS: 338 [MH]⁺

Example 1421-(2-Chloro-phenyl)-3-{6-[4-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea

The title compound is prepared analogously as described in Example 125Busing 4-(2-morpholin-4-yl-ethoxy)-phenylamine, crystallization from DCMafford the title compound.

White powder. HPLC: t_(R)=5.82 min (gradient I), ESI-MS: 469 [MH]⁺

Example 1433-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-ethyl-1-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

To a solution of 2,6-dichloro-3-methoxyphenylisocyanate (1.25 eq.) intoluene (1.9 ml) is addedN-ethyl-N′-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine(113 mg, 0.36 mmol), under an argon atmosphere. The resulting mixture isstirred at 70° C. for 18 h, allowed to cool to RT and filtered. Therecovered solid is washed with diethyl ether, dried and further purifiedby MPLC (silica gel) (DCM/MeOH) to afford 10 mg of the title compound asa white solid: ESI-MS: 559.9/561.9 [MH]⁺; t_(R)=3.53 min (purity: 100%,gradient J); TLC: R_(f)=0.28 (DCM/MeOH, 9:1).

A.N-Ethyl-N′-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine

A mixture of (6-chloro-pyrimidin-4-yl)-ethyl-amine (363 mg, 2.30 mmol,1.1 eq.) and 4-(4-methylpiperazin-1-yl)-aniline (400 mg, 2.09 mmol) inwater (0.8 ml) and glacial acetic acid (3.2 ml) is heated to 100° C. 3h. After solvent evaporation, the residue is taken up in methanol, madealkaline by addition of 25% NH₃ in water and concentrated. The residueis purified by MPLC (silica gel) (DCM/MeOH) to afford 395 mg of thetitle compound as a white solid: ESI-MS: 313.2 [MI-1]'; t_(R)=1.25 min(purity: ˜90%, gradient J); TLC: R_(f)=0.12 (DCM/MeOH, 9:1).

B. (6-Chloro-pyrimidin-4-yl)-ethyl-amine

Ethylamine (70% in water, 16 ml, 45.08 mmol, 2.5 eq.) is added dropwise(15 min) to a suspension of 4,6-dichloropyrimidine (12 g, 80.5 mmol) inEtOH (36 ml) at RT. The resulting yellowish solution is allowed to stirfor 1 h at RT and then cooled to 0° C. The resulting white precipitateis collected by vacuum filtration, washed with water and dried in vacuoto afford 12.4 g of the title compound: ESI-MS: 157.9 [MH]⁺; single peakat t_(R)=2.02 min (purity: 100%, gradient J).

Example 1443-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-dimethylaminomethyl-phenylamino)-pyrimidin-4-yl]-1-methyl-urea

2,6-dichloro-3,5-dimethoxyphenylisocyanate (1.25 eq.) is added to asolution ofN-(3-dimethylaminomethyl-phenyl)-N′-methyl-pyrimidine-4,6-diamine (93mg, 0.36 mmol, 1 eq.) in toluene (3 ml), at 70° C. and under an argonatmosphere. The resulting mixture is stirred at 70° C. for 18 h, allowedto cool to RT, and diluted with DCM and a saturated aqueous solution ofsodium bicarbonate. The aqueous layer is separated and extracted withDCM. The organic phase is washed with brine, dried (sodium sulfate),filtered and concentrated. Purification of the crude product by silicagel column chromatography (DCM/MeOH+1% NH₃ ^(aq), 9:1) affords 121 mg ofthe title compound as a white solid: ESI-MS: 504.9/506.9 [MH]⁺;t_(R)=3.64 min (purity: 100%, gradient J); TLC: R_(f)=0.12 (DCM/MeOH+1%NH₃ ^(aq), 9:1).

A. N-(3-Dimethylaminomethyl-phenyl)-N′-methyl-pyrimidine-4,6-diamine

A mixture of (6-chloro-pyrimidin-4-yl)-methyl-amine (Example 1) (750 mg,5.2 mmol), 3-dimethylaminomethyl-phenylamine (787 mg, 5.2 mmol) and 4NHCl in dioxane (15 ml) is heated in a sealed tube to 150° C. for 5 h.The reaction mixture is concentrated, diluted with DCM and a saturatedaqueous solution of sodium bicarbonate. The aqueous layer is separatedand extracted with DCM. The organic phase is washed with brine, dried(sodium sulfate), filtered and concentrated. Purification of the residueby silica gel column chromatography (DCM/MeOH+1% NH₃ ^(aq), 9:1) affords800 mg of the title compound as a white solid: ESI-MS: 258.1 [MH]⁺;t_(R)=1.00 min (purity: 100%, gradient J); TLC: R_(f)=0.14 (DCM/MeOH+1%NH₃ ^(aq), 9:1).

Example 1453-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea

The title compound is prepared as described in Example 144 but usingN-[4-(4-ethyl-piperazin-1-yl)-phenyl]-N-methyl-pyrimidine-4,6-diamine(2.39 g, 7.7 mmol, 1 eq.) and stirring the reaction mixture for 1.5 h atreflux. Purification of the crude product by silica gel columnchromatography (DCM/MeOH+1% NH₃ ^(aq), 95:5) affords the title compoundas a white solid: ESI-MS: 560.0/561.9 [MH]⁺; t_(R)=3.54 min (purity:100%, gradient J); TLC: R_(f)=0.28 (DCM/MeOH+1% NH₃ ^(aq), 95:5).

A.N-[4-(4-ethyl-piperazin-1-yl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 144A but using4-(4-ethylpiperazin-1-yl)-aniline (1 g, 4.88 mmol) and(6-chloro-pyrimidin-4-yl)-methyl-amine (Example 1) (771 1.81 g, 12.68mmol, 1.3 eq.). Purification of the residue by silica gel columnchromatography (DCM/MeOH, 93:7) followed by trituration in diethyl etheraffords the title compound as a white solid: ESI-MS: 313.2 [MH]⁺;t_(R)=1.10 min (gradient J); TLC: R_(f)=0.21 (DCM/MeOH, 93:7).

B. 4-(4-Ethylpiperazin-1-yl)-aniline

A suspension of 1-ethyl-4-(4-nitro-phenyl)-piperazine (6.2 g, 26.35mmol) and Raney Nickel (2 g) in MeOH (120 mL) is stirred for 7 h at RT,under a hydrogen atmosphere. The reaction mixture is filtered through apad of celite and concentrated to afford 5.3 g of the title compound asa violet solid: ESI-MS: 206.1 [MH]⁺; TLC: R_(f)=0.15 (DCM/MeOH+1% NH₃^(aq), 9:1).

C. 1-Ethyl-4-(4-nitro-phenyl)-piperazine

A mixture of 1-bromo-4-nitrobenzene (6 g, 29.7 mmol) and1-ethylpiperazine (7.6 ml, 59.4 mmol, 2 eq.) is heated to 80° C. for 15h. After cooling to RT, the reaction mixture is diluted with water andDCM/MeOH, 9:1. The aqueous layer is separated and extracted withDCM/MeOH, 9:1. The organic phase is washed with brine, dried (sodiumsulfate), filtered and concentrated. Purification of the residue bysilica gel column chromatography (DCM/MeOH+1% NH₃ ^(aq), 9:1) affords6.2 g of the title compound as a yellow solid: ESI-MS: 236.0 [MH]⁺;t_(R)=2.35 min (purity: 100%, gradient J); TLC: R_(f)=0.50 (DCM/MeOH+1%NH₃ ^(aq), 9:1).

Example 1463-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-(6-{4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenylamino}-pyrimidin-4-yl)-urea

The title compound is prepared as described in Example 144 but usingN-methyl-N′-{4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-pyrimidine-4,6-diamine(93 mg, 0.26 mmol, 1 eq.). Purification of the crude product by silicagel column chromatography (DCM/MeOH+1% NH₃ ^(aq), 95:5) affords 86 mg ofthe title compound as a white solid: ESI-MS: 603.9/605.9 [MH]⁺;t_(R)=3.21 min (purity: 100%, gradient J); TLC: R_(f)=0.19 (DCM/MeOH+1%NH₃ ^(aq), 95:5).

A.N-Methyl-N′-{4-[3-(4-methyl-Piperazin-1-yl)-propoxy]-phenyl}-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 143A but using4-[3-(4-methylpiperazin-1-yl)-propoxy]-phenylamine (383 mg, 1.50 mmol,1.1 eq.) and stirring the reaction mixture for 18 h at 100° C. Thereaction mixture is allowed to cool to RT, poured onto a saturatedaqueous solution of sodium bicarbonate, and extracted with EE and DCM.The organic phase is dried (sodium sulfate), filtered and concentrated.

The residue is triturated in diethyl ether to provide 115 mg of thetitle compound as a white solid: ESI-MS: 357.1 [MH]⁺; t_(R)=1.10 min(gradient J); purity: 100%, gradient J); TLC: R_(f)=0.08 (DCM/MeOH,9:1).

B. 4-[3-(4-Methylpiperazin-1-yl)-propoxyl]-phenylamine

1-(3-Chloro-propyl)-4-methyl-piperazine hydrochloride (1.7 g, 9.6 mmol,1.2 eq.) is added in one portion to a mixture of 4-aminophenol (893 mg,8.0 mmol) and finely powdered sodium hydroxide (808 mg, 20 mmol, 2.5eq.) in DMF (27 ml). The reaction mixture is stirred for 17 h at RT. Theresulting dark suspension is filtered. The filtrate is diluted with DCM(200 ml) and washed with brine (2×50 ml). The aqueous layer isback-extracted with DCM. The organic phase is dried (sodium sulfate),filtered and concentrated. Purification of the residue by silica gelcolumn chromatography (DCM/MeOH, 7:3) provides 1.86 g of the titlecompound as a yellow-brown oil: ESI-MS: 250.2 [MH]⁺, TLC: R_(f)=0.31(DCM/MeOH, 7:3).

Example 1473-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(3-dimethylamino-propyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea

The title compound is prepared as described in Example 144 but usingN-K-(3-dimethylamino-propyl)-phenyl]-N′-pyrimidine-4,6-diamine (206 mg,0.72 mmol, 1 eq.). Purification of the crude product by silica gelcolumn chromatography (DCM/MeOH+1% NH₃ ^(aq), 93:7) affords 84 mg of thetitle compound as a white solid: ESI-MS: 532.9/534.9 [MH]⁺; t_(R)=3.70min (purity: 100%, gradient J); TLC: R_(f)=0.15 (DCM/MeOH+1% NH₃ ^(aq),93:7).

A. N-[4-(3-Dimethylamino-propyl)-phenyl]-N′-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 144A but using4-(3-dimethylamino-propyl-phenylamine (311 mg, 1.7 mmol). Purificationof the residue by silica gel column chromatography (DCM/MeOH+1% NH₃^(aq), 9:1), followed by trituration of the resulting solid in diethylether, affords 213 mg of the title compound as a white solid: ESI-MS:286.1 [MH]⁺; t_(R)=1.20 min (gradient J); purity: 100%, gradient J);TLC: R_(f) 0.08 (DCM/MeOH+1% NH₃ ^(aq), 9:1).

B. 4-(3-Dimethylamino-propyl-phenylamine

A mixture of dimethyl-[3-(4-nitro-phenyl)-prop-2-ynyl]-amine (1.35 g,6.6 mmol), 10% palladium on carbon (140 mg), and EtOH (25 ml) is stirredfor 22 h at RT, under a hydrogen atmosphere. The reaction mixture isfiltered through a pad of celite and concentrated. Purification of theresidue by silica gel column chromatography (DCM/MeOH+1° A) NH₃ ^(aq),95:5) affords 797 mg of the title compound as a brown oil: ESI-MS: 179.0[MH]⁺; TLC: R_(f)=0.14 (DCM/MeOH+1% NH₃ ^(aq), 95:5).

C. Dimethyl-[3-(4-nitro-phenyl)-prop-2-ynyl]-amine

Tri-t-butylphosphine (0.25 M in dioxane, 11.9 ml, 3.0 mmol, 0.2 eq.),3-dimethylamino-1-propyne (2.2 ml, 20.8 mmol, 1.4 eq.), anddiisopropylamine (2.7 ml, 19.3 mmol, 1.3 eq.) are added sequentially toa mixture of 4-bromonitrobenzene (3 g, 14.9 mmol), copper (I) iodide(198 mg, 1.0 mmol, 0.07 eq.), and Pd(PhCN)₂Cl₂ (570 mg, 1.5 mmol, 0.1eq.) in dioxane (20 ml), under an argon atmosphere. The resultingmixture is stirred for 22 h at RT and concentrated. The residue isdissolved in EE and water and filtered through a pad of celite. Theaqueous layer is separated and extracted with EE. The organic phase iswashed with brine, dried (sodium sulfate), filtered and concentrated.Purification of the residue by silica gel column chromatography(DCM/MeOH+1% NH₃ ^(aq), 95:5) affords 2.72 g of the title compound as abrown oil: ESI-MS: 205.0 [MH]⁺; t_(R)=2.51 min (purity: 100%, gradientJ); TLC: R_(f)=0.41 (DCM/MeOH+1% NH₃ ^(aq), 95:5).

Example 1483-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea

The title compound is prepared as described in Example 144 but usingN-methyl-N′-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-4,6-diamine(227 mg, 0.72 mmol, 1 eq.). Purification of the crude product by silicagel column chromatography (DCM/MeOH+1% NH₃ ^(aq), 92:8) affords 156 mgof the title compound as a white solid: ESI-MS: 560.9/562.9 [MH]⁺;t_(R)=3.64 min (purity: 100%, gradient J); TLC: R_(f)=0.42 (DCM/MeOH+1%NH₃ ^(aq), 92:8).

A.N-Methyl-N′-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 143A but using4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (360 mg, 1.70 mmol, 1 eq.) andstirring the reaction mixture for 18 h at 150° C. The reaction mixtureis allowed to cool to RT and the top phase is discarded. The glueybottom residue is diluted with a saturated aqueous solution of sodiumbicarbonate and DCM. The aqueous layer is separated and extracted withDCM. The organic phase is dried (sodium sulfate), filtered andconcentrated. Purification of the crude product by silica gel columnchromatography (DCM/MeOH+1% NH₃ ^(aq), 9:1), followed by trituration ofthe resulting solid in diethyl ether, affords 402 mg of the titlecompound as a grey solid: ESI-MS: 314.1 [MH]⁺; t_(R)=1.15 min (gradientJ); purity: 100%, gradient J); TLC: R=0.15 (DCM/MeOH+1% NH₃ ^(aq), 9:1).

B. 4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamine

The title compound is prepared as described in Example 146B but using1-(2-chloroethyl)-pyrrolidine hydrochloride (7.6 g, 44.9 mmol, 1.2 eq.)and stirring the reaction mixture for 2 h at 75° C. Purification of theresidue by silica gel column chromatography (DCM/MeOH, 1:1) affords 7.7g of the title compound as a brown oil: ESI-MS: 207.1 [MH]⁺; TLC:R_(f)=0.22 (DCM/MeOH, 1:1).

Example 1493-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea

The title compound is prepared as described in Example 144 but usingN-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine(140 mg, 0.43 mmol, 1 eq.). Purification of the crude product by MPLC(silica gel) (DCM/MeOH+1% NH₃ ^(aq), 95:5) affords 24 mg of the titlecompound: ESI-MS: 573.9/575.9 [MH]⁺; t_(R)=3.25 min (purity: 90%,gradient J); TLC: R_(f)=0.09 (DCM/MeOH+1% NH₃ ^(aq), 9:1).

A.N-[4-(4-Ethyl-piperazin-1-ylmethyl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 143A but using4-(4-ethyl-piperazin-1-ylmethyl)-phenylamine (500 mg, 2.28 mmol, 1 eq.)and stirring the reaction mixture for 18 h at 150° C. Purification ofthe crude product by MPLC (silica gel) (DCM/MeOH+1% NH₃ ^(aq), 9:1)affords 140 mg of impure product which is used without furtherpurification.

B. 4-(4-Ethyl-piperazin-1-ylmethyl)-phenylamine

A suspension of 1-ethyl-4-(4-nitro-benzyl)-piperazine (7.2 g, 29.14mmol) and Raney Nickel (1.5 g) in MeOH (100 mL) is stirred for 6 h atRT, under a hydrogen atmosphere. The reaction mixture is filteredthrough a pad of celite and concentrated to afford 6.3 g of the titlecompound as a yellow solid: ESI-MS: 220.1 [MH]⁺; TLC: R_(f)=0.08(DCM/MeOH+1% NH₃ ^(aq), 9:1).

C. 1-Ethyl-4-(4-nitro-benzyl)-piperazine

A mixture of 4-nitrobenzylchloride (5 g, 29.14 mmol), N-ethylpiperazine(4.4 ml, 34.97 mmol, 1.2 eq.), potassium carbonate (8 g, 58.28, 2 eq.),and acetone (100 ml) is stirred for 15 h at reflux. The reaction mixtureis allowed to cool to RT, filtered and concentrated to afford 7.2 g ofthe title compound as a brow oil: ESI-MS: 250.1 [MH]⁺; TLC: R_(f)=0.31(DCM/MeOH+1% NH₃ ^(aq), 9:1).

Example 1503-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[3-(4-ethyl-piperazin-1-ylmethyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea

The title compound is prepared as described in Example 144 but usingN-[3-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine(306 mg, 0.94 mmol, 1 eq.). Purification of the crude product by MPLC(silica gel) (DCM/MeOH+1% NH₃ ^(aq), 95:5) affords 207 mg of the titlecompound: ESI-MS: 573.9/575.9 [MH]⁺; t_(R)=3.28 min (purity: 100%,gradient J); TLC: R_(f)=0.24 (DCM/MeOH+1% NH₃ ^(aq), 95:5).

A.N-[3-(4-Ethyl-piperazin-1-ylmethyl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 143A but using3-(4-ethyl-piperazin-1-ylmethyl)-phenylamine (500 mg, 2.28 mmol, 1 eq.)and stirring the reaction mixture for 15 h at 150° C. Purification ofthe crude product by MPLC (silica gel) (DCM/MeOH+1% NH₃ ^(aq), 9:1)affords 306 mg of the title compound as a beige solid: ESI-MS: 327.2[MH]⁺; TLC: R_(f)=0.05 (DCM/MeOH+1% NH₃ ^(aq), 9:1).

B. 3-(4-Ethyl-piperazin-1-ylmethyl)-phenylamine

The title compound is prepared as described in Example 149B: ESI-MS:220.1 [MH]⁺; t_(R)=0.79 min (purity: 100%, gradient J).

C. 1-Ethyl-4-(3-nitro-benzyl)-piperazine

The title compound is prepared as described in Example 149C: ESI-MS:250.1 [MH]⁺; t_(R)=1.50 min (purity: 100%, gradient J); TLC: R_(f)=0.32(DCM/MeOH+1% NH₃ ^(aq), 9:1).

Example 1513-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-dimethylaminomethyl-phenylamino)-pyrimidin-4-yl]-1-ethyl-urea

A suspension of 2,6-dichloro-3-methoxyphenylisocyanate (2 eq.) intoluene (3 ml) is added to a refluxing solution ofN-(3-dimethylaminomethyl-phenyl)-N′-methyl-pyrimidine-4,6-diamine (216mg, 0.80 mmol, 1 eq.) in toluene (3 ml), under an argon atmosphere. Theresulting mixture is stirred at reflux for 2 h and allowed to cool toRT. The reaction mixture is diluted with EE and a saturated aqueoussolution of sodium bicarbonate. The aqueous layer is separated andextracted with EE. The organic phase is washed with brine, dried (sodiumsulfate), filtered and concentrated. Purification of the residue bysilica gel column chromatography (DCM/MeOH+1% NH₃ ^(aq), 95:5), followedby reversed phase MPLC purification (AcCN/H₂O/TFA) of the resultingproduct, affords 161 mg of the title compound as a white solid: ESI-MS:518.9/520.9 [MH]⁺; t_(R)=3.76 min (purity: 100%, gradient J); TLC: R_(f)0.21 (DCM/MeOH+1% NH₃ ^(aq), 95:5).

A. N-(3-Dimethylaminomethyl-phenyl)-N′-ethyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 143A but using3-dimethylaminomethyl-phenylamine (334 mg, 2.20 mmol, 1 eq.),(6-chloro-pyrimidin-4-yl)-ethyl-amine (Example 143B) and stirring thereaction mixture for 3 h at 160° C. Purification of the crude product bysilica gel column chromatography (DCM/MeOH+1% NH₃ ^(aq), 9:1), followedby trituration of the resulting solid in diethyl ether, affords 335 mgof the title compound as a beige solid: ESI-MS: 272.1 [MH]⁺; t_(R)=1.18min (purity: 100%, gradient J); TLC: R_(f) 0.16 (DCM/MeOH+1% NH₃ ^(aq),9:1).

Example 1523-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea

The title compound is prepared as described in Example 151 but usingN-[4-(2-diethylamino-ethoxy)-phenyl]-N′-methyl-pyrimidine-4,6-diamine(255 mg, 0.81 mmol, 1 eq.). Purification of the crude product by silicagel column chromatography (DCM/MeOH+1% NH₃ ^(aq), 95:5), followed bytrituration of the resulting solid in MeOH, affords 220 mg of the titlecompound as a white solid: ESI-MS: 562.9/564.9 [MH]⁺; t_(R)=3.70 min(purity: 93%, gradient J); TLC: R_(f)=0.21 (DCM/MeOH+1% NH₃ ^(aq),95:5).

A. N-[4-(2-Diethylamino-ethoxy)-phenyl]-N′-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 143A but using4-(2-diethylamino-ethoxy)-phenylamine (271 mg, 1.3 mmol, 1 eq.) andstirring the reaction mixture for 18 h at 150° C. The reaction mixtureis allowed to cool to RT and the top phase is discarded. The glueybottom residue is diluted with a saturated aqueous solution of sodiumbicarbonate and DCM. The aqueous layer is separated and extracted withDCM. The organic phase is dried (sodium sulfate), filtered andconcentrated. Purification of the crude product by silica gel columnchromatography (DCM/MeOH+1% NH₃ ^(aq), 92:8) provides 261 mg of thetitle compound as a grey solid: ESI-MS: 316.1 [MH]⁺; t_(R)=1.25 min(purity: 100%, gradient J); TLC: R_(f)=0.19 (DCM/MeOH+1% NH₃ ^(aq),92:8).

B. 4-(2-Diethylamino-ethoxy)-phenylamine

The title compound is prepared as described in Example 146B but using1-(2-chloroethyl)-diethylamine hydrochloride (1.9 g, 11 mmol, 1.2 eq.)and stirring the reaction mixture for 1 h at RT. Purification of theresidue by silica gel column chromatography (DCM/MeOH, 4:1→7:3) affords1.52 g of the title compound as a brown oil: ESI-MS: 209.1 [MH]⁺; TLC:R_(f)=0.12 (DCM/MeOH, 7:3).

Example 1533-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(2,6-dimethyl-pyridin-3-ylamino)-pyrimidin-4-yl]-1-methyl-urea

The title compound is prepared as described in Example 151 but usingN-(2,6-dimethyl-pyridin-3-yl)-N′-methyl-pyrimidine-4,6-diamine.

ESI-MS: 476.9/478.9 [MH]⁺; t_(R)=3.44 min (purity: 100%, gradient J);TLC: R_(f)=0.40 (DCM/MeOH+1% NH₃ ^(aq), 9:1).

A. N-(2,6-Dimethyl-pyridin-3-yl)-N′-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 152A but using3-amino-2,6-dimethylpyrimidine and stirring the reaction mixture for 24h at 150° C.

ESI-MS: 230.1 [MH]⁺; TLC: R_(f)=0.22 (DCM/MeOH, 9:1).

Example 1543-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyrimidin-4-yl]-urea

The title compound is prepared as described in Example 151 but usingN-methyl-N′-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine-4,6-diamine.

ESI-MS: 514.8/516.8 [MH]⁻; t_(R)=5.27 min (purity: 100%, gradient J);TLC: R_(f)=0.49 (DCM/MeOH, 9:1).

A. N-Methyl-N′-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 152A but using3-amino-6-(trifluoromethyl)pyridine and stirring the reaction mixturefor 24 h at 150° C.

ESI-MS: 270.0 [MH]⁺; t_(R)=2.63 min (purity: 100%, gradient J); TLC:R_(f)=0.32 (DCM/MeOH, 9:1).

Example 1551-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea

The title compound is prepared as described in Example 151 but usingN-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-4,6-diamine.

ESI-MS: 546.9/548.8 [MH]; t_(R)=3.15 min (purity: 100%, gradient J);TLC: R_(f)=0.49 (DCM/MeOH+1% NH₃ ^(aq), 95:5).

A. N-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 152A but using6-chloro-pyrimidin-4-ylamine, 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine(Example 148B), and stirring the reaction mixture for 2 h at 150° C.

ESI-MS: 300.1 [MH]⁺; t_(R)=1.10 min (purity: 100%, gradient J).

Example 1563-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-ethyl-1-{6-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea

The title compound is prepared as described in Example 151 but usingN-ethyl-N′-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-4,6-diamine.

ESI-MS: 575.2/577.2 [MH]⁺; t_(R)=3.74 min (purity: 100%, gradient J);TLC: R_(f)=0.42 (DCM/MeOH+1% NH₃ ^(aq), 95:5).

A.N-Ethyl-N′-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 152A but using6-chloro-pyrimidin-4-yl)-ethyl-amine,4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (Example 148B), and stirringthe reaction mixture for 6 h at 150° C. The crude product is purified bytrituration in diethyl ether.

ESI-MS: 326.1 [MH]⁻; t_(R)=1.45 min (purity: 95%, gradient J).

Example 1571-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-[6-(3-dimethylaminomethyl-phenylamino)-pyrimidin-4-yl]-urea

The title compound is prepared as described in Example 151 but usingN-(3-dimethylaminomethyl-phenyl)-pyrimidine-4,6-diamine.

ESI-MS: 491.0/493.0 [MH]⁺; t_(R)=3.17 min (purity: 97%, gradient J);TLC: R_(f)=0.25 (DCM/MeOH+1% NH₃ ^(aq), 92:8).

A. N-(3-Dimethylaminomethyl-phenyl)-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 152A but using3-dimethylaminomethyl-phenylamine, 6-chloro-pyrimidin-4-ylamine, andstirring the reaction mixture for 2 h at 150° C. The crude product ispurified by trituration in diethyl ether followed by silica gel columnchromatography (DCM/MeOH+1% NH₃ ^(aq), 92:8) of the resulting beigesolid to afford the title compound as a white solid. ESI-MS: 242.1[MH]⁻; t_(R)=0.95 min (purity: 100%, gradient J); TLC: R_(f)=0.11(DCM/MeOH+1% NH₃ ^(aq), 92:8).

Example 1581-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-(6-{4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenylamino}-pyrimidin-4-yl)-urea

The title compound is prepared as described in Example 151 but usingN-(3-dimethylaminomethyl-phenyl)-pyrimidine-4,6-diamine.

ESI-MS: 575.9/577.9 [MH]⁺; t_(R)=2.83 min (purity: 100%, gradient J);TLC: R_(f)=0.03 (DCM/MeOH+1% NH₃ ^(aq), 95:5).

A.N-{4-[2-(4-Methyl-piperazin-1-yl)-ethoxy]-phenyl}-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 152A but using4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenylamine (300 mg, 1.28 mmol, 1eq.), 6-chloro-pyrimidin-4-ylamine, water (0.5 ml), and stirring thereaction mixture for 2 h at 150° C. The crude product is purified bytrituration in diethyl ether to afford the title compound as a whitesolid. ESI-MS: 329.1 [MH]⁺; t_(R)=0.98 min (purity: 100%, gradient J).

Example 1591-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-[6-(4-dimethylaminomethyl-3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-urea

The title compound is prepared as described in Example 151 but usingN-(4-dimethylaminomethyl-3-trifluoromethyl-phenyl)-pyrimidine-4,6-diamine.

ESI-MS: 558.9/560.9 [MH]⁺; t_(R)=3.69 min (purity: 100%, gradient J);TLC: R_(f)=0.21 (DCM/MeOH+1% NH₃ ^(aq), 95:5).

A.N-(4-Dimethylaminomethyl-3-trifluoromethyl-phenyl)-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 152A but using4-dimethylaminomethyl-3-trifluoromethyl-phenylamine (218 mg, 1.46 mmol,1 eq.), 6-chloro-pyrimidin-4-ylamine, and stirring the reaction mixturefor 5 h at 150° C. The crude product is purified by silica gel columnchromatography (DCM/MeOH+1% NH₃ ^(aq), 92:8) to afford the titlecompound as a white solid. ESI-MS: 312.1 [MH]⁺; t_(R)=1.20 min (purity:100%, gradient J); TLC: R_(f)=0.16 (DCM/MeOH+1% NH₃ ^(aq), 92:8).

B. 4-(4-(N,N-Dimethylamino-methyl)-3-trifluoromethyl-phenyl-amine

N-(4-Dimethylaminomethyl-3-trifluoromethyl-phenyl)-pyrimidine-4,6-diamine(359 mg, 1.2 mmol) is dissolved in MeOH (12 mL) and treated with K₂CO₃(6 mL of a 1N aqueous solution) at RT. The reaction is heated to refluxfor 1.5 h until completion, cooled back to RT and concentrated. Theresidual oil is taken up in EtOAc and washed with brine. The organiclayers are dried over Na₂SO₄, filtered and concentrated under reducedpressure. Drying under high vacuum gives the title compound as a yellowoil. ESI-MS: 219 [MH]⁺.

C.N-(4-Dimethylaminomethyl-3-trifluoromethyl-phenyl)-pyrimidine-4,6-diamine

501 mg (1.5 mmol)N-(4-bromomethyl-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide(Step 14.2) is added to 5 ml of a solution of dimethyl amine in EtOH(33%) at RT. The reaction is stirred at ambient temperature for 0.5 huntil completion. It is concentrated and the residual crude product ispurified by flash chromatography (SiO₂; CH₂Cl₂/MeOH, gradient 0-5% MeOH)to give the title compound as a yellow oil. ESI-MS: 315 [MH]⁺.

D. N-(4-Bromomethyl-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide

To a solution of 60.9 g (224.6 mmol) ofN-(4-methyl-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide in 830ml n-butyl acetate under a nitrogen atmosphere, 44 g (247 mmol)N-bromosuccinimide and 830 mg (5 mmol) azo-iso-butyronitrile are added.The suspension is heated up to 60° C. and then illuminated for 30 min bya Phillips low-voltage lamp (500 W; 10500 lm), whereby the temperaturerises to 70-75° C. and a clear brown solution is formed. There is stillremaining educt detectable, therefore another 22 g N-bromosuccinimideare added in 3 portions. After totally 6 h illumination, the resultingsolid is filtered off and discarded and the filtrate concentrated. Theresidue is distributed between 2 l CH₂Cl₂ and 1 l H₂O and the aqueouslayer extracted with 1 l CH₂Cl₂. The organic phases are washed 4 timeswith 1 l H₂O, 0.5 l brine, dried (Na₂SO₄) and concentrated. Columnchromatography (SiO₂; hexane/CH₂Cl₂ 2:1→1:1) and crystallization fromCH₂Cl₂/hexane yields the title compound: m.p.: 119-120° C.

E. N-(4-Methyl-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide

To an ice-cooled solution of 320 g (1.827 Mol) of5-amino-2-methylbenzotrifluoride and 1.47 l (18.27 mol) pyridine in 4.5l of CH₂Cl₂ under N₂-atmosphere, 284 ml (2.01 Mol) of trifluoroaceticacid anhydride are added dropwise. After 50 min, the mixture is dilutedwith 5 l ice-cooled 2 N HCl. The organic phases are separated off andwashed two times with 2 l cold 2 N HCl, then 1 l 2 N HCl and finallywith 2 l brine. The aqueous layers are extracted twice with CH₂Cl₂, theorganic phases dried (Na₂SO₄) and concentrated partially.Crystallization by addition of hexane yields the title compound: m.p.:72-73° C.

Example 1601-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

2,6-dichloro-3,5-dimethoxyphenylisocyanate (1.2 eq.) is added to asolution of N-[4-(4-ethyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine(350 mg, 1.18 mmol) in NMP (2 ml), at 70° C. and under an argonatmosphere. The resulting mixture is stirred at 70° C. for 2 h, allowedto cool to RT and concentrated. The residue is diluted with DCM and asaturated aqueous solution of sodium bicarbonate. The aqueous layer isseparated and extracted with DCM. The organic phase is washed withbrine, dried (sodium sulfate), filtered and concentrated. Purificationof the crude product by trituration in MeOH followed by silica gelcolumn chromatography (DCM/MeOH+1% NH₃ ^(aq), 97:3) affords the titlecompound as a white solid: ESI-MS: 545.9/547.9 [MH]⁺; t_(R)=3.10 min(purity: 100%, gradient J); TLC: R_(f)=0.18 (DCM/MeOH+1% NH₃ ^(aq),95:5).

A. N-(4-(4-Ethyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine

A mixture of 6-chloro-pyrimidin-4-yl)-amine (500 mg, 3.87 mmol, 1.3 eq.)and 4-(4-ethylpiperazin-1-yl)-aniline (611 mg, 2.98 mmol) in water (3.0ml) and glacial acetic acid (10 ml) is heated to 100° C. for 15 h. Thereaction mixture is diluted with DCM and brine. The aqueous layer ismade basic by addition of sodium bicarbonate. The aqueous layer isseparated and extracted with DCM. The organic phase is washed withbrine, dried (sodium sulfate), filtered and concentrated. Purificationof the crude product by trituration in EE affords the title compound:ESI-MS: 299.2 [MH]⁺; t_(R)=1.05 min (gradient J).

Example 1613-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[3-(4-isopropyl-piperazin-1-ylmethyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea

The title compound is prepared as described in Example 151 but usingN-[3-(4-isopropyl-piperazin-1-ylmethyl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine.Purification of the crude product by MPLC (silica gel) (DCM/MeOH+1% NH₃^(aq), 95:5) affords the title compound as a white solid: ESI-MS:587.9/589.9 [MH]⁺; t_(R)=3.35 min (purity: 100%, gradient J); TLC:R_(f)=0.17 (DCM/MeOH+1% NH₃ ^(aq), 9:1).

A.N-[3-(4-Isopropyl-piperazin-1-ylmethyl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 152A but using3-(4-isopropyl-piperazin-1-ylmethyl)-phenylamine and stirring thereaction mixture for 17.5 h at 150° C. The crude product is purified byMPLC (silica gel) (DCM/MeOH+1% NH₃ ^(aq), 95:5) to afford the titlecompound as a light yellow solid. ESI-MS: 341.2 [MH]⁺; t_(R)=1.05 min(purity: 100%, gradient J); TLC: R_(f)=0.10 (DCM/MeOH+1% NH₃ ^(aq),9:1).

B. 3-(4-Isopropyl-Piperazin-1-ylmethyl)-phenylamine

The title compound is prepared as described in Example 149B: ESI-MS:234.2 [MH]⁺.

C. 1-Isopropyl-4-(3-nitro-benzyl)-piperazine

The title compound is prepared as described in Example 149C.Purification of the crude product by silica gel column chromatography(DCM/MeOH+1% NH₃ ^(aq), 9:1) affords the title compound as a yellowsolid: ESI-MS: 264.1 [MH]⁺; t_(R)=1.64 min (purity: 96.5%, gradient J);TLC: R_(f)=0.35 (DCM/MeOH+1% NH₃ ^(aq), 9:1).

Example 1623-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-phenylamino)-pyrimidin-4-yl]-1-methyl-urea

The title compound is prepared as described in Example 151 but usingN-(3-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-N′-methyl-pyrimidine-4,6-diamine.Purification of the crude product by MPLC (silica gel) (DCM/MeOH+1% NH₃^(aq), 95:5) affords the title compound as a white solid: ESI-MS:561.9/563.9 [MH]⁺; t_(R)=3.24 min (purity: 100%, gradient J); TLC:R_(f)=0.10 (DCM/MeOH+1% NH₃ ^(aq), 9:1).

A.N-(3-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-N′-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 152A but usingN-(3-amino-benzyl)-N,N′,N′-trimethyl-ethane-1,2-diamine and stirring thereaction mixture for 17.5 h at 150° C. The crude product is purified byMPLC (silica gel) (DCM/MeOH+1% NH₃ ^(aq), 95:5) to afford the titlecompound as a beige solid. ESI-MS: 315.2 [MH]⁺; TLC: R_(f)=0.05(DCM/MeOH+1 NH₃ ^(aq), 9:1).

B. N-(3-Amino-benzyl)-N,N′,N′-trimethyl-ethane-1,2-diamine

The title compound is prepared as described in Example 149B: ESI-MS:208.2 [MH]⁺.

C. N,N′,N′-Trimethyl-N′-(3-nitro-benzyl)-ethane-1,2-diamine

The title compound is prepared as described in Example 149C.Purification of the crude product by silica gel column chromatography(DCM→DCM/MeOH+1% NH₃ ^(aq), 9:1) affords the title compound as a brownoil: ESI-MS: 238.1 [MH]⁺; t_(R)=1.15 min (purity: 96.5%, gradient J);TLC: R_(f)=0.10 (DCM/MeOH, 9:1).

Example 1633-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea

The title compound is prepared as described in Example 151 but usingN-[4-(4-isopropyl-piperazin-1-yl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine.

ESI-MS: 573.9/575.9 [MH]⁺; t_(R)=3.65 min (purity: 97%, gradient J);TLC: R_(f)=0.10 (DCM/MeOH+1% NH₃ ^(aq), 97:3).

A.N-[4-(4-Isopropyl-piperazin-1-yl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 152A but usingN-(3-amino-benzyl)-N,N′,N′-trimethyl-ethane-1,2-diamine and stirring thereaction mixture for 4 h at 150° C. The crude product is purified bysilica gel column chromatography (DCM/MeOH+1% NH₃ ^(aq), 92:8) to affordthe title compound as a white solid. ESI-MS: 327.2 [MH]⁺; TLC:R_(f)=0.26 (DCM/MeOH+1% NH₃ ^(aq), 92:8).

B. 4-(4-Isopropyl-piperazin-1-yl)-phenylamine

The title compound is prepared as described in Example 149B: ESI-MS:220.1 [MH]⁺.

C. 1-Isopropyl-4-(4-nitro-phenyl)-piperazine

The title compound is prepared as described in Example 149C.Purification of the crude product by silica gel column chromatography(DCM/MeOH, 95:5) affords the title compound as a yellow solid: ESI-MS:238.1 [MH]⁺; t_(R)=2.57 min (purity: 100%, gradient J); TLC: R_(f)=0.16(DCM/MeOH, 95:5).

Example 1641-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(1-methyl-piperidin-4-yloxy)-phenylamino]-pyrimidin-4-yl}-urea

Example 1653-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-{6-[4-(1-methyl-piperidin-4-yloxy)-phenylamino]-pyrimidin-4-yl}-urea

Example 1663-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-ethyl-{6-[4-(1-methyl-piperidin-4-yloxy)-phenylamino]-pyrimidin-4-yl}-urea

Example 1673-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(4-dimethylaminomethyl-3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-1-methyl-urea

Example 1681-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamino]-pyrimidin-4-yl}-urea

Example 1693-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamino]-pyrimidin-4-yl}-1-methyl-urea

Example 170 In Vitro Enzymatic Data

The compounds of Examples 1 to 169 were tested under the protocols ashereinbefore described for their inhibitory activity against KDR, FGFR3and TEK. Measurements are made as described in the aforementionedmethods in the general description. For KDR 67-100% inhibition at 10 μM,for FGFR3 (K650E) 27-100% inhibition at 10 μM and for Tek 12-100%inhibition at 10 μM is observed.

Method A Examples 171-193 Example 171N-[4-Methyl-3-(3-methyl-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide

To a solution of N-(3-Amino-4-methyl-phenyl)-3-trifluoromethyl-benzamide(preparation 3, 62 mg, 0.21 mmol, 1.25 eq.) in dioxane is added 20%phosgene solution in toluene (110 μl, 0.21 mmol, 1.25 eq.) under argon.The reaction mixture is stirred for further 22 h at room temperatureunder argon. Then, the solvent is evaporated and the residue is taken upin dry toluene (2 ml). After the addition ofN-Methyl-N′-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine(50 mg, 0.168 mmol, 1.0 eq.) the suspension is refluxed for 24 h underargon. After cooling ether (2 ml) is added and the mixture is stirredfor 30 min. The precipitated product is filtered off, washed (1×toluene/ether 1:1, 1× ether) and vacuum dried at 60° C. overnight toafford the title compound as colorless crystals: M.p. 189.5-191° C.,HPLC: t_(R)=6.02 min (purity: >99%, gradient A), ESI-MS: 619.6 [MH]⁺.

N-Methyl-N′-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine

A solution of (6-chloro-pyrimidin-4-yl)-methyl-amine (1.65 g, 11.5 mmol,1.1 eq.) and commercially available 4-(4-methylpiperazin-1-yl)-aniline(2.0 g, 10.5 mmol, 1.0 eq.) in a mixture of water (4 ml) and glacialacetic acid (16 ml) is heated to 100° C. internal temperature for 16 h.After cooling the solvent is evaporated.

The residue is taken up in methanol (50 ml) and made alkaline byaddition of 25% NH₃ in water. To this silica gel (11 g) is added and thesolvent is evaporated. The silica adsorbed crude product is purified bymedium pressure liquid chromatography (A: TBME; B: MeOH—NH₃ 99:1;gradient: 5% B->25% B in 180 min). The fractions containing the productare pooled and evaporated to dryness. The residue is triturated withether. The product is filtered off, washed with ether, and vacuum driedat 50° C. over night to give the title compound as pale yellow powder:t_(R)=3.04 min (purity: 97%, gradient A), ESI-MS: 299.3 [MH]⁺.

(6-chloro-pyrimidin-4-yl)-methyl-amine

This material was prepared by a modified procedure published in theliterature (J. Appl. Chem. 1955, 5, 358): To a suspension ofcommercially available 4,6-dichloropyrimidine (20 g, 131.6 mmol, 1.0eq.) in isopropanol (60 ml) is added 33% methylamine in ethanol (40.1ml, 328.9 mmol, 2.5 eq.) at such a rate that the internal temperaturedoes not rise above 50° C. After completion of the addition the reactionmixture was stirred for 1 h at room temperature. Then, water (50 ml) isadded and the suspension formed is chilled in an ice bath to 5° C. Theprecipitated product is filtered off, washed with cold isopropanol/water2:1 (45 ml) and water. The collected material is vacuum dried over nightat 45° C. to afford the title compound as colorless crystals: t_(R)=3.57min (purity: >99%, gradient A), ESI-MS: 144.3/146.2 [MH]⁺.

By following the procedure of Example 171 but using the appropriatestarting materials, examples 172-193 may be prepared:

Example 172N-{4-Methyl-3-[3-(6-methylamino-pyrimidin-4-yl)-ureido]-phenyl}-3-trifluoromethyl-benzamide

Colorless crystals, TLC: R_(f)=0.40 (TBME/MeOH/NH3 90:9:1), HPLC:t_(R)=5.88 min (purity: 85%, gradient A), ESI-MS: 445.4 [MH]⁺.

Example 173N-{4-Methyl-3-[3-(6-phenylamino-pyrimidin-4-yl)-ureido]-phenyl}-3-trifluoromethyl-benzamide

Colorless crystals, HPLC: t_(R)=6.94 min (purity: >99%, gradient A),ESI-MS: 507.4 [MH]⁺.

Example 174N-[4-Methyl-3-(3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide

Colorless crystals, TLC: R_(f)=0.53 (TBME/MeOH/NH3 80:18:2), HPLC:t_(R)=5.79 min (purity: >99%, gradient A), ESI-MS: 605.5 [MH]⁺.

Example 175N-[4-Methyl-3-(3-{6-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide

Colorless crystals, TLC: R_(f)=0.34 (TBME/MeOH/NH3 80:18:2), HPLC:t_(R)=5.72 min (purity: >99%, gradient A), ESI-MS: 605.5 [MH]⁺.

Example 176N-[2-(3-{6-[4-(2-Diethylamino-ethoxy)-phenylamino]-pyrimidin-4-yl}-ureido)-4-methyl-phenyl]-3-trifluoromethyl-benzamide

Colorless crystals, TLC: R_(f)=0.63 (TBME/MeOH/NH3 80:18:2), HPLC:t_(R)=5.84 min (purity: >99%, gradient A), ESI-MS: 622.4 [MH]⁺.

Example 177N-[3-(3-{6-[4-(3-Dimethylamino-propoxy)-phenylamino]-pyrimidin-4-yl}-ureido]-4-methyl-phenyl]-3-trifluoromethyl-benzamide

Colorless crystals, HPLC: t_(R)=5.75 min (purity: >99%, gradient A),ESI-MS: 608.4 [MH]⁺.

Example 178N-[3-(3-{6-[3-(2-Dimethylamino-ethoxy)-phenylamino]-pyrimidin-4-yl}-ureido)-4-methyl-phenyl]-3-trifluoromethyl-benzamide

Colorless crystals, TLC: R_(f)=0.17 (TBME/MeOH 30:70), HPLC: t_(R)=5.72min (purity: 95%, gradient A), ESI-MS: 594.5 [MH]⁺.

Example 179N-[4-Methyl-3-(3-{6-[4-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide

Colorless crystals, TLC: R_(f)=0.31 (TBME/MeOH 80:20), HPLC: t_(R)=5.66min (purity: >99%, gradient A), ESI-MS: 636.5.4 [MH]⁺.

Example 180N-[4-Methyl-3-(3-{6-[3-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide

Colorless crystals, TLC: R_(f)=0.42 (TBME/MeOH 75:25), HPLC: t_(R)=5.86min (purity: >99%, gradient A), ESI-MS: 636.6 [MH]⁺.

Example 181N-{4-Methyl-3-[3-methyl-3-(6-phenylamino-pyrimidin-4-yl)-ureido]-phenyl}-3-trifluoromethyl-benzamide

Colorless crystals, TLC: R_(f)=0.69 (TBME/MeOH90:10), HPLC: t_(R)=7.67min (purity: >99%, gradient A), ESI-MS: 521.4 [MH]⁺.

Example 182N-[3-(3-{6-[3-(2-Dimethylamino-ethoxy)-phenylamino]-pyrimidin-4-yl}-3-methyl-ureido)-4-methyl-phenyl]-3-trifluoromethyl-benzamide

Colorless crystals, TLC: R_(f)=0.51 (TBME/MeOH/NH3 80:18:2), HPLC:t_(R)=6.02 min (purity: >99%, gradient A), ESI-MS: 608.4 [MH]⁺.

Example 183N-[3-(3-{6-[4-(2-Diethylamino-ethoxy)-phenylamino]-pyrimidin-4-yl}-3-methyl-ureido)-4-methyl-phenyl]-3-trifluoromethyl-benzamide

Colorless crystals, TLC: R_(f)=0.24 (TBME/MeOH 75:25), HPLC: t_(R)=6.23min (purity: 94%, gradient A), ESI-MS: 636.5 [MH]⁺.

Example 184N-{4-Methyl-3-[3-methyl-3-(6-{4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenylamino}-pyrimidin-4-yl)-ureido]-phenyl}-3-trifluoromethyl-benzamide

Colorless crystals, TLC: R_(f)=0.21 (DCM/MeOH 80:20), HPLC: t_(R)=6.07min (purity: 88%, gradient A), ESI-MS: 633.2 [MH]⁺.

Example 185N-{4-Methyl-3-[3-methyl-3-(6-{3-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenylamino}-pyrimidin-4-yl)-ureido]-phenyl}-3-trifluoromethyl-benzamide

Colorless crystals, HPLC: t_(R)=6.15 min (purity: 92%, gradient A),ESI-MS: 633.3 [MH]⁺.

Example 1864-Methyl-3-(3-methyl-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-ureido)-N-(3-trifluoromethyl-phenyl)-benzamide

Colorless powder, HPLC: t_(R)=6.19 min (purity: 96%, gradient A),ESI-MS: 619.3 [MH]⁺.

Example 187N-[4-Methyl-3-(3-methyl-3-{6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-pyrimidin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide

Colorless crystals, TLC: R_(f)=0.50 (DCM/MeOH 80:20), HPLC: t_(R)=5.82min (purity: 88%, gradient A), ESI-MS: 647.6 [MH]⁺.

Example 188N-[4-Methyl-3-(3-methyl-3-{6-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide

Pale yellow crystals, TLC: R_(f)=0.50 (TBME/MeOH/NH3 80:18:2), HPLC:t_(R)=6.14 min (purity: 95%, gradient A), ESI-MS: 619.5 [MH]⁺.

Example 189N-{4-Methyl-3-[3-[2-(4-methyl-piperazin-1-yl)-ethyl]-3-(6-phenylamino-pyrimidin-4-yl)-ureido]-phenyl}-3-trifluoromethyl-benzamide

Colorless crystals, TLC: R_(f)=0.04 (TBME/MeOH 90:10), HPLC: t_(R)=6.26min (purity: >100%, gradient A), ESI-MS: 633.5 [MH]⁺.

Example 190N-{4-Methyl-3-[3-(6-phenylamino-pyrimidin-4-yl)-3-(2-pyridin-2-yl-ethyl)-ureido]-phenyl}-3-trifluoromethyl-benzamide

Colorless crystals, HPLC: t_(R)=7.58 min (purity: >100%, gradient A),ESI-MS: 612.4 [MH]⁺.

Example 191N-{4-Methyl-3-[3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimid-in-4-yl}-3-(2-pyridin-2-yl-ethyl)-ureido]-phenyl}-3-trifluoromethyl-benzamide

Pink crystals, TLC: R_(f)=0.54 (DCM/MeOH 80:20), HPLC: t_(R)=5.87 min(purity: 92%, gradient A), ESI-MS: 710.6 [MH]⁺.

Example 192N-[3-(3-Ethyl-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-ureido)-4-methyl-phenyl]-3-trifluoromethyl-benzamide

Colorless crystals, TLC: R_(f)=0.45 (DCM/MeOH 80:20), HPLC: t_(R)=6.18min (purity: >100%, gradient A), ESI-MS: 633.6 [MH]⁺.

Example 193N-[4-Methyl-3-(3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimid-in-4-yl}-3-thiophen-2-ylmethyl-ureido)-phenyl]-3-trifluoromethyl-benzamide

Colorless crystals, TLC: R_(f)=0.26 (DCM/MeOH 90:10), HPLC: t_(R)=6.51min (purity: >100%, gradient A), ESI-MS: 701.5 [MH]⁺.

Method B Examples 194-201 Example 194N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-methyl-ureido]-4-methyl-phenyl}-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide

To tert-butyl[6-(1-Methyl-3-{2-methyl-5-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoro-methyl-benzoylamino]-phenyl}-ureido)-pyrimidin-4-yl]-carbamate(50 mg, 0.076 mmol) is added trifluoroacetic acid/DCM 2:3 (2 ml). Theclear reaction mixture is stirred for 1 h at room temperature. Then,methanol/DCM 1:9 (20 ml) is added. The solution is washed with 50%aqueous K₂CO₃, dried over MgSO₄ and evaporated to give the titlecompound as a beige powder: M.p. 191.5-193° C., HPLC: t_(R)=5.27 min(purity: >99%, gradient A), ESI-MS: 557.3 [MH]⁺, 400 MHz ¹H-NMR(DMSO-d₆) δ: 2.19 (s, 3H, NMe), 2.30 (s, 3H, ArMe), 2.24-2.62 (br m, 8H,piperazine), 3.32 (s, 3H, urea-NMe), 3.69 (s, 2H, ArCH₂N), 6.09 (s, 1H,pyrimidine-H5), 7.02 (s, 2H, NH₂), 7.19 (d, 1H, Ar—H5), 7.50 (dd, 1H,Ar—H4), 7.91 (d, 1H, Ar′—H5), 8.23 (dd, 1H, Ar′—H6), 8.26 (d, 1H,Ar—H2), 8.30 (s, 1H, pyrimidine-H2), 8.41 (d, 1H, Ar′—H2), 10.41 (s, 1H,amide-NH).

tert-Butyl[6-(1-Methyl-3-{2-methyl-5-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoro-methyl-benzoylamino]-phenyl}-ureido)-pyrimidin-4-yl]-carbamate

To a solution of4-(4-Methyl-piperazin-1-ylmethyl)-2-trifluoromethyl-benzoic acid(Preparation 2, 80 mg, 0.27 mmol, 1.1 eq.) in DMA is added HATU (138 mg,0.36 mmol, 1.5 eq.) and diisopropylethylamine (83 μl, 0.48 mmol, 2.0eq.) after 10 min stirring at room temperature tert-butyl{6-[3-(5-Amino-2-methyl-phenyl)-1-methyl-ureido]-pyrimidin-4-yl}-carbamateis added. The reaction mixture is sonicated for 5 min. After stirring atroom temperature over night a grey suspension is formed. The precipitateis filtered off, washed with DMA and ether. Vacuum drying at 60° C. overnight afforded a gray powder: HPLC: t_(R)=6.30 min (purity: >99%,gradient A), ESI-MS: 657.4 [MH]⁺.

tert-Butyl{6-[3-(5-Amino-2-methyl-phenyl)-1-methyl-ureido]-pyrimidin-4-yl}-carbamate

A solution of tert-butyl{6-[3-(2-methyl-5-nitro-phenyl)-1-methyl-ureido]-pyrimidin-4-yl}-carbamate(330 mg, 0.82 mmol) in a mixture of methanol (20 ml) and DMF (50 ml) ishydrogenated in the presence of 10% palladium on charcoal (500 mg) atatmospheric pressure. After 20 h the hydrogenation is complete and thecatalyst is filtered off. The filtrate is evaporated to dryness. Theresidue obtained is triturated with ether, filtered off, and vacuumdried to afford a gray powder: HPLC: t_(R)=5.38 min (purity: 97%,gradient A), ESI-MS: 373.4 [MH]⁺.

tert-Butyl{6-[3-(2-methyl-5-nitro-phenyl)-1-methyl-ureido]-pyrimidin-4-yl}-carbamate

A solution of tert-butyl (6-Methylamino-pyrimidin-4-yl)-carbamate (240mg, 1.07 mmol, 1.0 eq.), commercially available2-methyl-5-nitrophenylisocyanate (210 mg, 1.18 mmol, 1.1 eq.), and DMAP(26 mg, 0.21 mmol, 0.2 eq.) in toluene (10 ml) is stirred at 80° C. for24 h. After cooling to room temperature methanol (10 ml) is added andthe suspension formed is stirred for 10 min at 50° C. The precipitate isfiltered off and washed with methanol (2×10 ml). After drying in vacuoan extremely insoluble colorless powder is obtained: HPLC: t_(R)=8.09min (purity: 85%, gradient A), ESI-MS: 403.5 [MH]⁺.

tert-Butyl (6-Methylamino-pyrimidin-4-yl)-carbamate

A solution ofbis(tert-butyl)-(6-chloro-4-pyrimidinyl)-imidodicarboxylate (1 g, 3.03mmol, 1.0 eq.) in 33% methylamine in ethanol (5.63 ml, 45.5 mmol, 15eq.) is heated to 80° C. in a sealed tube for 2 h and then allowed toreach room temperature. The precipitated product is filtered off, washedwith cold ethanol and vacuum dried at 60° C. over night. The titlecompound is obtained as colorless crystals: HPLC: t_(R)=3.82 min(purity: 99%, gradient A), ESI-MS: 225.1 [MH]^(+ (weak),) 169.1[MH-tBu]⁺.

Bis(tert-butyl)-(6-chloro-4-pyrimidinyl)-imidodicarboxylate may beprepared according to a procedure published in the literature: J. M.Lehn et al., Eur. J. Chem. 2001, 1515-1521.

By following the procedure of Example 194 but using the appropriatestarting materials, examples 195-201 may be prepared:

Example 195N-{4-Methyl-3-[3-methyl-3-(6-phenylamino-pyrimidin-4-yl)-ureido]-phenyl}-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide

Beige crystals, HPLC: t_(R)=6.33 min (purity: 96%, gradient A), ESI-MS:633.8 [MH]⁺.

Example 1963-(5-Amino-2-methoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

Beige crystals, TLC: R_(f)=0.19 (DCM/MeOH 85:15), HPLC: t_(R)=3.72 min(purity: >100%, gradient A), ESI-MS: 463.6 [MH]⁺.

Example 197N-[4-Methoxy-3-(3-methyl-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide

Pale yellow crystals, TLC: R_(f)=0.21 (TBME/MeOH 60:40), HPLC:t_(R)=5.94 min (purity: 97%, gradient A), ESI-MS: 635.2 [MH]⁺.

Example 198N-[4-Methoxy-3-(3-methyl-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-ureido)-phenyl]-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoro-methyl-benzamide

Pale yellow crystals, TLC: R_(f)=0.19 (TBME/MeOH/NEt3 50:50:1.5), HPLC:t_(R)=5.07 min (purity: 96%, gradient A), ESI-MS: 747.4 [MH]⁺.

Example 199N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-methyl-ureido]-5-methoxy-phenyl}-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide

Colorless crystals, HPLC: t_(R)=5.12 min (purity: 97%, gradient A),ESI-MS: 573.2 [MH]⁺.

Example 200N-{3-Methoxy-5-[3-methyl-3-(6-phenylamino-pyrimidin-4-yl)-ureido]-phenyl}-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide

Yellow resin, HPLC: t_(R)=6.20 min (purity: 99%, gradient A), ESI-MS:649.4 [MH]⁺.

Example 201N-[3-Methoxy-5-(3-methyl-3-{6-[4-(4-methyl-piperazin-1-yl)-phenyl-amino]-pyrimidin-4-yl}-ureido)-phenyl]-4-methyl-3-trifluoromethyl-benzamide

Beige crystals, TLC: R_(f)=0.39 (DCM/MeOH 85:15), HPLC: t_(R)=6.17 min(purity: >100%, gradient A), ESI-MS: 649.7 [MH]⁺.

Example 202N-[3-[3-(6-Acetylaminopyrimidin-4-yl)-3-methylureido]-4-methylphenyL]-4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylbenzamide

colourless crystalline solid, TLC: R_(f)=0.24 (DCM/EtOH/NH3 90:9:1),HPLC: t_(R)=10.57 min (purity: 100%, gradient B), ESI-MS: 599 [MH]⁺.

Example 203[6-(1-Methyl-3-{2-methyl-5-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzoylamino]-phenyl}-ureido)-pyrimidin-4-yl]-carbamicacid methyl ester

Colourless powder, TLC: R_(f)=0.20 (DCM/EtOH/NH3 90:9:1), HPLC:t_(R)=11.25 min (purity: 100%, gradient B), ESI-MS: 615 [MH]⁺.

Example 204[6-(1-Methyl-3-{2-methyl-5-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylcarbamoyl]-phenyl}-ureido)-pyrimidin-4-yl]-carbamicacid methyl ester

Colourless powder, TLC: R_(f)=0.33 (DCM/EtOH/NH3 90:9:1), HPLC:t_(R)=10.97 min (purity: 100%, gradient B), ESI-MS: 615 [MH]⁺.

Example 2053-[3-(6-Acetylamino-pyrimidin-4-yl)-3-methyl-ureido]-4-methyl-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-benzamide

Example 2063-[3-(6-Amino-pyrimidin-4-yl)-3-methyl-ureido]-4-methyl-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-benzamide

Example 207 In Vitro Inhibition Data

The compounds of Examples 171 to 206 were tested under the protocols ashereinbefore described for their inhibitory activity against c-Abl, KDRand FGFR3. For c-Abl 79-100% inhibition at 10 μM, for KDR 87-100%inhibition at 10 μM and for FGFR3 56-98% inhibition at 10 μM isobserved.

Example 208N-[4-Methyl-3-(3-methyl-3-{6-[(tetrahydro-furan-2-ylmethyl)-amino]-pyrimidin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide

Pal-resin bearing C-(Tetrahydro-furan-2-yl)-methylamine (1 g, 1 mmol),DIEA (0.52 mL, 3 mmol), and 4,6-dichloropyrimidine (300 mg, 2 mmol) aremixed in n-BuOH (15 mL). The reaction vial is put into a heating shakerand heated up at 80° C. for 16 hours. The resultant mixture is filteredand the resin is washed with DMF (3×20 mL), MeOH (3×20 mL), CH₂Cl₂ (3×20mL), and dried under vacuum. 10 mgs of the resin is treated withTFA/CH₂Cl₂/H₂O (45/50/5) (200 μL) for 1 hour. LC-MS revealed only onemajor peak: observed MS (M+H⁺) is 214.2;

Pal-resin bearing (6-Chloro-pyrimidin-4 yl)(tetrahydro-furan-2-ylmethyl)-amine (1 mmol), 40% methylamine watersolution (1.95 mL, 25 mmol), 15 mL n-BuOH are mixed together in a sealedtube. The reaction vial is put into a heating shaker and heated up at100° C. for 12 hours. After cooling, another 1.95 mL of 40% methylaminewater solution is added into the reaction vial. The reaction is heatedto 100° C. for 12 hours. The resultant mixture is filtered and the resinis washed with DMF (3×20 mL), MeOH (3×20 mL), CH₂Cl₂ (3×20 mL), anddried under vacuum. 10 mgs of the resin is treated with TFA/CH₂Cl₂/H₂O(45/50/5) (200 μL) for 1 hour. LC-MS revealed only one major peak:observed MS (M+H⁺) is 209.2.

Pal-resin bearingN-Methyl-N′-(tetrahydro-furan-2-ylmethyl)-pyrimidine-4,6-diamine (1mmol), 2-methyl-5-nitrophenyl-isocyanate (540 mg, 3 mmol), DIEA (0.52mL, 3 mmol), 15 mL anhydrous DMF are mixed together. The reaction vialis heated with shaking to 60° C. for 14 hours. The resultant mixture isfiltered and the resin is washed with DMF (3×20 mL), MeOH (3×20 mL),CH₂Cl₂ (3×20 mL), and dried under vacuum. 10 mgs of the resin is treatedwith TFA/CH₂Cl₂/H₂O (45/50/5) (2004) for 1 hour. LC-MS revealed only onemajor peak: observed MS (M+H) is 387.2.

Pal-resin bearing 1-Methyl 3 (2methyl-5-nitro-phenyl)-1-{6-[(tetrahydro-furan-2-ylmethyl)-amino]-pyrimidin-4-yl}-urea(1 mmol), tin(II) chloride (1.55 g, 8 mmol), 15 mL NMP are mixedtogether. The reaction vial is shaken at room temperature for 16 hours.The resultant mixture is filtered and the resin is washed with DMF (3×20mL), MeOH (3×20 mL), CH₂Cl₂ (3×20 mL), and dried under vacuum. 10 mgs ofthe resin is treated with TFA/CH₂Cl₂/H₂O (45/50/5) (200 μL) for 1 hour.LC-MS revealed only one major peak: observed MS (M+H⁺) is 357.3.

Pal-resin bearing3-(5-Amino-2-methyl-phenyl)-1-methyl-1-{6-[(tetrahydro-furan-2-ylmethyl)-amino]-pyrimidin-4-yl}-urea(1 mmol), 3-trifluoromethyl-benzoyl chloride (630 mg, 3 mmol), DIEA(0.52 mL, 3 mmol) and 15 mL anhydrous DMF are mixed together. Thereaction vial is shaking in room temperature for 16 hours. The resultantmixture is filtered and the resin is washed with DMF (3×20 mL), MeOH(3×20 mL), CH₂Cl₂ (3×20 mL), and dried under vacuum. 10 mgs of the resinis treated with TFA/CH₂Cl₂/H₂O (45/50/5) (2004) for 1 hour. LC-MSrevealed only one major peak: observed MS (M+H⁺) is 529.3.

All of the pal resin is treated with TFA/CH₂Cl₂/H₂O (45/50/5) (10 mL)for 2 hours. After removing the solvent under the vacuum, the crudeproduct is dissolved in DMSO and purified by reverse phase preparativeHPLC to give the final product N-[4-Methyl 3 (3methyl-3-{6-[(tetrahydro-furan-2-ylmethyl)-amino]-pyrimidin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamideas the white solid, 241 mg. A summary of the procedure is described inthe flow diagram below. The solid spheres indicate a solid support (Palresin); ¹H NMR (600 MHz, DMSO-d₆) δ 12.84 (s, 1H), 10.44 (s, 1H), 8.41(s, 1H), 8.34 (s, 1H), 8.28 (s, 1H), 8.27 (d, J=7.9 Hz, 1H), 7.96 (d,J=8.0 Hz, 1H), 7.78 (t, J=7.4 Hz, 1H), 7.60 (s, 1H), 7.51 (d, J=8.2 Hz,1H), 7.20 (d, J=8.0 Hz, 1H), 6.16 (s, 1H), 3.92-3.79 (m, 3H), 3.64-3.62(m, 2H), 3.34 (s, 3H), 2.31 (s, 3H), 1.85-1.82 (m, 4H); ESIMS m/z 529.3(M⁺+1).

Example 209N-(3-{3-[6-(Benzo[1,3]dioxol-5-ylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide

The general procedure is as same as example 208, except the Pal-resin isattached to benzo[1,3]dioxol-5-ylamine. All of the pal resin is treatedwith TFA/CH₂Cl₂/H₂O (45/50/5) (10 mL) for 2 hours. After removing thesolvent under the vacuum, the crude product is dissolved into DMSO andpurified by reverse phase preparative HPLC to give the final productN-(3-{3-[6-(Benzo[1,3]dioxol-5-ylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamideas the white solid; ¹H NMR (400 MHz, DMSO-d₆) δ 12.70 (s, 1H), 10.44 (s,1H), 9.58 (s, 1H), 8.49 (s, 1H), 8.40 (d, J=11.8 Hz, 2H), 8.30 (s, 1H),8.27 (d, J=7.8 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.78 (t, J=7.8 Hz, 1H),7.51 (d, J=8.4 Hz, 1H), 7.37 (t, J=8.1 Hz, 1H), 7.25 (d, J=8.8 Hz, 1H),6.88 (d, J=8.3 Hz, 1H), 6.35 (s, 1H), 6.00 (s, 2H), 3.33 (s, 3H), 2.32(s, 3H); ESIMS m/z 565.3 (M⁺+1).

in which R represents an R₇ substituent as defined in the Summary of theInvention.

Example 210N-(3-{3-[6-(3-Dimethylamino-phenylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-methyl-phenyl]-3-trifluoromethyl-benzamide

A reaction scheme for this protocol is shown above.4,6-dichloropyrimidine (1.0 g, 6.75 mmol), 2.0M methylamine in MeOH(3.38 mL, 6.75 mmol) and DIEA (1.76 mL, 10.13 mmol) are dissolved in 30mL ethanol. The reaction is heated to 70° C. for 4 hours. After removingthe solvent, the crude product is purified by flash chromatography usingEA/Hexane (3:7) to get the final product(6-Chloro-pyrimidin-4-yl)-methyl-amine as the white solid.

(6-Chloro-pyrimidin 4 yl)methyl-amine (940 mg, 6.57 mmol),2-methyl-5-nitrophenyl-isocyanate (1.23 g, 6.90 mmol), DIEA (2.30 mL,13.15 mmol) are dissolved in 30 mL anhydrous DMF. The reaction isstirred in room temperature for 14 hours. After removing the solvent,the crude product is purified by flash chromatography using EA/Hexane(4:6) to get the final product 1-(6-Chloro-pyrimidin-4-yl)-1-methyl-3-(2methyl-5-nitro-phenyl)-urea as the white solid.

1-(6-Chloro-pyrimidin-4-yl)-1-methyl-3-(2 methyl-5-nitro-phenyl)-urea(100 mg, 0.31 mmol), N,N-Dimethyl-benzene-1,3-diamine HCl salt (82 mg,0.47 mmol) are dissolved in 6 mL n-BuOH. The reaction is heated up to90° C. for 16 hours. After removing the solvent, the crude product ispurified by flash chromatography using EA/Hexane (1:1) to get the finalproduct1-[6-(3-dimethylamino-phenylamino)-pyrimidin-4-yl]-1-methyl-3-(2-methyl-5-nitro-phenyl)-ureaas white solid.

1-[6-(3-Dimethylamino-phenylamino)-pyrimidin-4-yl]-1-methyl-3-(2-methyl-5-nitro-phenyl)-urea(110 mg, 0.26 mmol) and 10 mg 10% palladium carbon powder are mixed in20 mL EtOH under hydrogen environment. The reaction is stirred at 50° C.for 4 hours. The reaction mixture is passed through a celite plug andwashed by methanol. After removing the solvent under the vacuum, thecrude product3-(5-Amino-2-methyl-phenyl)-1-[6-(3-dimethylamino-phenylamino)-pyrimidin-4-yl]-1-methyl-ureais used for next step reaction without purification.

3-(5-Amino-2-methyl-phenyl)-1-[6-(3-dimethylamino-phenylamino)-pyrimidin-4-yl]-1-methyl-urea(0.26 mmol), 3-trifluoromethyl-benzoyl chloride (57 mg, 0.27 mmol) andDIEA (68 uL, 0.39 mmol) are dissolved in 10 mL anhydrous DMF. Thereaction is stirred in the room temperature for 4 hours. After removingthe solvent, the crude product is dissolved into DMSO and purified byreverse phase preparative HPLC to give the final productN-(3-{3-[6-(3-Dimethylamino-phenylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamideas the white solid; ¹H NMR (600 MHz, DMSO-d₆) δ 12.67 (s, 1H), 10.44 (s,1H), 9.84 (s, 1H), 8.56 (s, 1H), 8.40 (d, J=11.8 Hz, 2H), 8.28 (s, 1H),8.24 (d, J=8.2 Hz, 1H), 7.94 (d, J=7.7 Hz, 1H), 7.76 (t, J=7.8 Hz, 1H),7.48 (d, J=8.4 Hz, 1H), 7.35 (t, J=8.1 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H),6.81 (d, J=7.5 Hz, 1H), 6.64 (s, 1H), 6.59 (d, J=8.2 Hz, 1H), 3.35 (s,3H), 2.92 (s, 6H), 2.35 (s, 3H); ESIMS m/z 565.3 (M⁺+1).

Example 211N-(3-{3-[6-(3-Acetylamino-phenylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide

The general procedure is as same as example 3, exceptN-(3-Amino-phenyl)-acetamide (71 mg, 0.47 mmol) and 0.12 mL 4M HCl indioxane solution are added in the reaction. The final productN-(3-{3-[6-(3-Acetylamino-phenylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamideis purified by reverse phase preparative HPLC to give the white solid;¹H NMR (600 MHz, DMSO-d₆) δ 12.67 (s, 1H), 10.44 (s, 1H), 9.84 (s, 1H),8.56 (s, 1H), 8.40-8.36 (m, 2H), 8.31 (s, 1H), 8.28 (d, J=7.8 Hz, 1H),8.07 (s, 1H), 7.95 (d, J=7.7 Hz, 1H), 7.84 (d, J=6.6 Hz, 1H), 7.78 (t,J=7.8 Hz, 1H), 7.52 (d, J=6.6 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.41 (t,J=7.8 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 6.48 (s, 1H), 3.37 (s, 3H), 2.79(d, J=4.2, 3H), 2.34 (s, 3H); ESIMS m/z 578.3 (M⁺+1).

Example 212N-(4-Methyl-3-{3-methyl-3-[6-(4-morpholin-4-yl-phenylamino)-pyrimidin-4-yl]-ureido}-phenyl)-3-trifluoromethyl-benzamide

4-methyl-3-nitroaniline (3.0 g, 20 mmol) is dissolved in 100 mlmethylene chloride. 3 ml triethylamine (22 mmol) is added, the solutionis cooled to 0° C., and 3-trifluorobenzioc chloride (4.1 g; 20 mmol) isadded slowly to the above mixture while stirring. The reaction mixturewas allowed raised to room temperature and the reaction was completed in1 hr. The reaction mixture was washed with 10% NaHCO₃ solution, brineand dried over Na₂SO₄. The final product (3)N-(4-Methyl-3-nitro-phenyl)-3-trifluoromethyl-benzamide is a yellowsolid, 6.28 g.

N-(4-Methyl-3-nitro-phenyl)-3-trifluoromethyl-benzamide (6.2 g, 19 mmol)was dissolved in 80 ml ethanol and 600 mg Pd/C was added to thesolution. The mixture was stirred under hydrogen at room temperature for4 hours. The Pd/C was removed by filtration. The crude product wasrecrystallized in ethyl acetate. The final product (4)N-(3-Amino-4-methyl-phenyl)-3-trifluoromethyl-benzamide is dark solid,5.5 g. 4,6-dichloro-pyrimidine (10 g, 67 mmol) was dissolved in 50 mlmethanol. Then 37 ml 2M methylamine THF solution was added to it. Thereaction was stirred for 10 hours at room temperature. The solvent wasremoved by rotary evaporation and the crude product was recrystallizedin methanol. The final product (5) (6-Chloro-pyrimidin-4-yl)methylaminewas light yellow solid, 8.2 g.

(6-Chloro-pyrimidin-4-yl)methyl-amine (1.43 g 10 mmol) was dissolved in20 ml dioxane and mixed with 1.7 ml DIEA (15 mmol), then 1.2 gtriphosgene was added to the solution. The reaction mixture was stirredat 85° C. for 3 hours. The reaction mixture was cooled down to roomtemperature. To this reaction mixture, 1.7 ml DIEA and 2.94 gN-(3-Amino-4-methyl-phenyl)-3-trifluoromethyl-benzamide (4) were added.The reaction was stirred at room temperature for 3 hours. The crudeproduct was recrystallized in ethyl acetate. The final product (8)N-{3-[3-(6-Chloro-pyrimidin-4-yl)-3-methyl-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamideis light yellow solid, 3.9 g.

N-{3-[3-(6-Chloro-pyrimidin-4-yl)-3-methyl-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide(50 mg, 0.107 mmol) and p-toluenesulfonic acid (20 mg, 0.105 mmol) weremixed and dissolved in 1 ml DMF. Then 4-Morpholin-4-yl-phenylamine (22mg, 0.11 mmol) was added to it. The reaction was stirred at 80° C. for10 hours. The crude product was purified by reverse phase HPLC to givefinal productN-(4-Methyl-3-{3-methyl-3-[6-(4-morpholin-4-yl-phenylamino)-pyrimidin-4-yl]-ureido}-phenyl)-3-trifluoromethyl-benzamideas grey solid, 48 mg; ¹H NMR 600 MHz (DMSO) δ 12.74 (s, 1H), 10.46 (s,1H), 9.53 (s, 1H), 8.47 (s, 1H), 8.41 (m, 1H), 8.31 (s, 1H), 8.28 (d,1H, J=7.8 Hz), 7.97 (d, 1H, J=7.2 Hz), 7.79 (t, 1H, J=4.2 Hz), 7.52 (d,1H, J=7.8 Hz), 7.47 (d, 2H, J=8.4 Hz), 7.22 (d, 1H, J=8.4 Hz), 6.99 (s,1H), 6.98 (s, 1H), 6.34 (s, 1H), 4.15 (m, 4H), 3.76 (m, 4H), 3.10 (m,3H), 2.32 (s, 3H); MS m/z 606.2 (M+1).

Example 213N-[4-Methyl-3-(3-methyl-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamide

This compound was made using the same procedure as above, except thatthe 4-(4-Methyl-piperazin-1-yl)-phenylamine was used instead of4-Morpholin-4-yl phenylamine. The final compoundN-[4-Methyl-3-(3-methyl-3-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-ureido)-phenyl]-3-trifluoromethyl-benzamideis white solid, 43 mg; ¹H NMR 600 MHz (DMSO) δ 12.75 (s, 1H), 10.47 (s,1H), 9.64 (s, 1H), 9.55 (s, 1H), 8.47 (s, 1H), 8.41 (m, 1H), 8.31 (s,1H), 8.28 (d, 1H, J=7.8 Hz), 7.97 (d, 1H, J=7.2 Hz), 7.79 (t, 1H, J=4.2Hz), 7.52 (d, 1H, J=7.8 Hz), 7.47 (d, 2H, J=8.4 Hz), 7.22 (d, 1H, J=8.4Hz), 6.99 (s, 1H), 6.98 (s, 1H), 6.34 (s, 1H), 3.79 (m, 2H), 3.56 (m,4H), 3.18 (m, 3H), 2.95 (m, 2H), 2.87 (s, 3H), 2.33 (s, 3H); MS m/z620.2 (M+1).

Example 214N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-(2-morpholin-4-yl-ethyl)-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide

Rink resin with free amino group (50 g, 53 mmol) is mixed with4,6-dichloropyrimidine (23 g, 159 mmol) in 60 ml butanol and 28 ml DIEA.The reaction mixture was shaken on heating block at 50° C. for 10 hours.The resin was washed with DMF, methanol and methylene chloride. Then to1 g of the resin is added 3 equivalent amine and 3 ml butanol, thereaction was shaken at 90° C. for 10 hours. The resin was washed withDMF, methanol and methylene chloride.

N-(3-Amino-4-methyl-phenyl)-3-trifluoromethyl-benzamide (880 mg, 3 mmol)was dissolved in 8 ml dioxane with 0.52 ml DIEA added. Then triphosgene(357 mg, 1.2 mmol) was added to this solution. The reaction was stirredat room temperature for 1 hour. This reaction mixture was then added tothe above resin. The reaction was shaken at 60° C. for 10 hours. Theresin was washed with DMF, methanol and methylene chloride. The resinwas cleaved with TFA at room temperature for 1 hour. The crude productwas purified by RP-HPLC.

Example 214 is prepared using 2-morpholin-4-yl-ethylamine as amine inthe procedure above. The final productN-{3-[3-(6-Amino-pyrimidin-4-yl)-3-(2-morpholin-4-yl-ethyl)-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamidewas white solid, 63 mg; ¹H NMR 600 MHz (DMSO) δ 12.95 (s, 1H), 10.46 (s,1H), 8.41 (s, 1H), 8.31 (s, 1H), 8.28 (s, 1H), 8.27 (s, 1H), 7.95 (d,1H, J=7.7 Hz), 7.77 (t, 1H, J=7.8 Hz), 7.54 (d, 1H, J=6.8 Hz), 7.20 (d,2H, J=8.3 Hz), 7.03 (s, 2H), 6.99 (s, 1H), 6.17 (s, 1H), 3.98 (s, 2H),3.59 (s, 4H), 3.35 (m, 2H), 2.50 (m, 4H), 2.30 (s, 3H); MS m/z 544.2(M+1).

Example 215N-(3-{3-(6-Amino-pyrimidin-4-yl)-3-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide

This compound was prepared using 1-(3-Amino-propyl)-pyrrolidin-2-one asamine in the procedure above. The final productN-(3-{3-(6-Amino-pyrimidin-4-yl)-3-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamideis white solid, 14 mg; ¹H NMR 600 MHz (DMSO) δ 12.51 (s, 1H), 10.40 (s,1H), 8.38 (s, 1H), 8.31 (s, 1H), 8.28 (s, 1H), 8.27 (s, 1H), 7.95 (d,1H, J=7.7 Hz), 7.77 (t, 1H, J=7.8 Hz), 7.54 (d, 1H, J=6.8 Hz), 7.20 (d,2H, J=8.3 Hz), 7.03 (s, 2H), 6.99 (s, 1H), 6.17 (s, 1H), 3.70 (m, 2H),3.31 (t, 2H, J=7.2 Hz), 3.24 (t, 2H, J=7.2 Hz), 2.23 (s, 3H), 2.16 (t,2H, J=8.4 Hz), 1.87 (m, 2H), 1.74 (m, 2H); MS m/z 556.2 (M+1).

Example 216

By repeating the procedures described in the above examples 208 to 215,using appropriate starting materials, the following compounds of FormulaI, as identified in Table 1, are obtained.

TABLE 1 Compound Number Structure Physical Data 1

¹H NMR (400 MHz, CD₃OH-d₄) δ 9.92 (d, J = 5.1 Hz, 1H), 9.80 (s, 1H),9.20 (d, J = 8.1 Hz, 2H), 8.93 (d, J = 8.5 Hz, 2H), 8.85 (d, J = 8.6 Hz,2H), 8.79 (d, J = 5.0 Hz, 2H), 8.76 (d, J = 8.0 Hz, 2H), 8.75 (s, 1H),8.46 (t, J = 9.0 Hz, 1H), 8.08 (s, 1H), 4.92 (s, 2H), 4.71 (s, 2H), 3.66(m, 6H); ESIMS m/z 623.20 (M⁺ + 1). 2

¹H NMR (600 MHz, DMSO- d₆) δ 12.82 (s, 1H), 10.44 (s, 1H), 8.40 (s, 1H),8.36 (s, 1H), 8.31 (s, 1H), 8.28 (d, J = 7.9 Hz, 1H), 7.96 (d, J = 7.8Hz, 1H), 7.78 (t, 7.8 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.40 (d, J =8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.1 Hz, 1H), 6.21(s, 1H), 4.57 (s, 2H), 3.18 (s, 3H), 2.39 (s, 3H); ESIMS m/z 569.10(M⁺ + 1). 3

¹H NMR (600 MHz, DMSO- d₆) δ 12.85 (s, 1H), 10.44 (s, 1H), 8.41 (s, 1H),8.34 (s, 1H), 8.31 (s, 1H), 8.28 (d, J = 7.4 Hz, 1H), 7.96 (d, J = 7.7Hz, 1H), 7.78 (t, J = 7.9 Hz, 1H), 7.62 (s, 1H), 7.51 (d, J = 8.1 Hz,1H), 7.33 (s, 1H), 7.31 (d, J = 7.1 Hz, 1H), 7.28 (s, 1H), 7.27 (s, 1H),7.22 (d, J = 9.2 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 6.15 (s, 1H), 3.30(m, 2H), 3.18 (s, 3H), 2.86 (t, J = 6.7 Hz, 2H), 2.24 (s, 3H); ESIMS m/z549.20 (M⁺ + 1). 4

¹H NMR (600 MHz, DMSO- d₆) δ 12.83 (s, 1H), 10.44 (s, 1H), 8.40 (s, 1H),8.36 (s, 1H), 8.31 (s, 1H), 8.27 (d, J = 7.9 Hz, 1H), 7.99 (s, 1H), 7.96(d, J = 7.5 Hz, 1H), 7.78 (t, J = 7.7 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H),7.28 (s, 1H), 7.27 (s, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.91 (s, 1H), 6.90(s, 1H), 6.15 (s, 1H), 4.50 (s, 2H), 3.73 (s, 3H), 3.29 (s, 3H), 2.20(3H); ESIMS m/z 565.20 (M⁺ + 1). 5

¹H NMR (600 MHz, DMSO- d₆) δ 12.86 (s, 1H), 10.44 (s, 1H), 8.41 (s, 1H),8.35 (br, 1H), 8.31 (s, 1H), 8.28 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 7.9Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.54 (s, 1H), 7.51 (d, J = 8.2 Hz,1H), 7.20 (d, J = 8.3 Hz, 2H), 6.12 (s, 1H), 3.34 (s, 3H), 3.31 (t, J =7.0 Hz, 2H), 3.25 (t, J = 7.0 Hz, 4H), 2.31 (s, 3H), 2.22 (t, J = 8.1Hz, 2H), 1.93 (dt, J = 7.6, 14.1 Hz, 2H), 1.73 (m, 2H); ESIMS m/z 570.20(M⁺ + 1). 6

ESIMS m/z 559.10 (M⁺ + 1). 7

ESIMS m/z 549.20 (M⁺ + 1). 8

ESIMS m/z 572.30 (M⁺ + 1). 9

ESIMS m/z 513.20 (M⁺ + 1). 10

ESIMS m/z 572.30 (M⁺ + 1). 11

ESIMS m/z 550.20 (M⁺ + 1). 12

ESIMS m/z 487.20 (M⁺ + 1). 13

ESIMS m/z 525.20 (M⁺ + 1). 14

¹H NMR (400 MHz, DMSO- d₆) δ 10.47 (s, 1H), 8.40 (d, J = 2.1 Hz, 1H),8.33 (s, 1H), 8.31-8.25 (m, 2H), ), 7.96 (t, J = 7.8 Hz, 1H), 7.78 (t, J= 7.8 Hz, 1H), 7.54 (d, J = 6.0, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.21 (d,J = 8.3 Hz, 2H) 6.13 (s, 1H), 3.31 (s, 3H), 2.31 (s, 3H), 2.17 (s, 2H);ESIMS m/z 445.10 (M⁺ + 1). 15

ESIMS m/z 488.10 (M⁺ + 1). 16

ESIMS m/z 567.10 (M⁺ + 1). 17

ESIMS m/z 553.10 (M⁺ + 1). 18

ESIMS m/z 517.10 (M⁺ + 1). 19

ESIMS m/z 502.20 (M⁺ + 1). 20

ESIMS m/z 579.20 (M⁺ + 1). 21

ESIMS m/z 552.10 (M⁺ + 1). 22

ESIMS m/z 603.10 (M⁺ + 1). 23

ESIMS m/z 579.15 (M⁺ + 1). 24

ESIMS m/z 578.30 (M⁺ + 1). 25

ESIMS m/z 515.20 (M⁺ + 1). 26

ESIMS m/z 558.30 (M⁺ + 1). 27

ESIMS m/z 485.20 (M⁺ + 1). 28

ESIMS m/z 564.20 (M⁺ + 1). 29

ESIMS m/z 578.20 (M⁺ + 1). 30

ESIMS m/z 633.30 (M⁺ + 1). 31

ESIMS m/z 620.30 (M⁺ + 1). 32

ESIMS m/z 670.30 (M⁺ + 1). 33

ESIMS m/z 499.2 (M⁺ + 1). 34

ESIMS m/z 515.2 (M⁺ + 1). 35

ESIMS m/z 528.3 (M⁺ + 1). 36

ESIMS m/z 537.2 (M⁺ + 1). 37

ESIMS m/z 503.2 (M⁺ + 1). 38

ESIMS m/z 522.2 (M⁺ + 1). 39

ESIMS m/z 536.2 (M⁺ + 1). 40

ESIMS m/z 516.2 (M⁺ + 1). 41

ESIMS m/z 542.30 (M⁺ + 1). 42

ESIMS m/z 614.30 (M⁺ + 1). 43

ESIMS m/z 558.30 (M⁺ + 1). 44

ESIMS m/z 553.30 (M⁺ + 1). 45

ESIMS m/z 649.30 (M⁺ + 1). 46

ESIMS m/z 649.30 (M⁺ + 1). 47

ESIMS m/z 558.30 (M⁺ + 1). 48

ESIMS m/z 558.30 (M⁺ + 1). 49

ESIMS m/z 403.30 (M⁺ + 1). 50

ESIMS m/z 403.30 (M⁺ + 1). 51

ESIMS m/z 403.30 (M⁺ + 1). 52

ESIMS m/z 403.30 (M⁺ + 1). 53

ESIMS m/z 495.3 (M⁺ + 1). 54

ESIMS m/z 479.30 (M⁺ + 1).

1. Assays

Compounds of Examples 208 to 216 are assayed to measure their capacityto selectively inhibit cell proliferation of 32D cells expressingBCR-Abl (32D-p210) compared with parental 32D cells. Compoundsselectively inhibiting the proliferation of these BCR-Abl transformedcells are tested for anti-proliferative activity on Ba/F3 cellsexpressing either wild type or the mutant forms of Bcr-abl. In addition,compounds are assayed to measure their capacity to inhibit FGFR35 (in anenzyme and cellular assay), FLT3, PDGFR13, trkB, c-SRC, BMX, SGK, Tie2,Lck, JNK2a2, MKK4, c-RAF, MKK6, SAPK2a and SAPK213 kinases.

Inhibition of Cellular BCR-Abl Dependent Proliferation (High ThroughputMethod)

The murine cell line used is the 32D hemopoietic progenitor cell linetransformed with BCR-Abl cDNA (32D-p210). These cells are maintained inRPMI/10% fetal calf serum (RPMI/FCS) supplemented with penicillin 50μg/mL, streptomycin 50 μg/mL and L-glutamine 200 mM. Untransformed 32Dcells are similarly maintained with the addition of 15% of WEHIconditioned medium as a source of IL3.

50 μl of a 32D or 32D-p210 cells suspension are plated in Greiner 384well microplates (black) at a density of 5000 cells per well. 50n1 oftest compound (1 mM in DMSO stock solution) is added to each well(STI571 is included as a positive control). The cells are incubated for72 hours at 37° C., 5% CO₂. 10 μl of a 60% Alamar Blue solution (Tekdiagnostics) is added to each well and the cells are incubated for anadditional 24 hours. The fluorescence intensity (Excitation at 530 nm,Emission at 580 nm) is quantified using the Acquest™ system (MolecularDevices).

Inhibition of Cellular BCR-Abl Dependent Proliferation

32D-p210 cells are plated into 96 well TC plates at a density of 15,000cells per well. 50 μL of two fold serial dilutions of the test compound(C_(max) is 40 μM) are added to each well (STI571 is included as apositive control). After incubating the cells for 48 hours at 37° C., 5%CO₂, 15 μL of MTT (Promega) is added to each well and the cells areincubated for an additional 5 hours. The optical density at 570 nm isquantified spectrophotometrically and IC₅₀ values, the concentration ofcompound required for 50% inhibition, determined from a dose responsecurve.

Effect on Cell Cycle Distribution

32D and 32D-p210 cells are plated into 6 well TC plates at 2.5×10⁶ cellsper well in 5 ml of medium and test compound at 1 or 10 μM is added(STI571 is included as a control). The cells are then incubated for 24or 48 hours at 37° C., 5% CO₂. 2 ml of cell suspension is washed withPBS, fixed in 70% EtOH for 1 hour and treated with PBS/EDTA/RNase A for30 minutes. Propidium iodide (Cf=10 μg/ml) is added and the fluorescenceintensity is quantified by flow cytometry on the FACScalibur™ system (BDBiosciences). Test compounds of the present invention demonstrate anapoptotic effect on the 32D-p210 cells but do not induce apoptosis inthe 32D parental cells.

Effect on Cellular BCR-Abl Autophosphorylation

BCR-Abl autophosphorylation is quantified with capture Elisa using ac-abl specific capture antibody and an antiphosphotyrosine antibody.32D-p210 cells are plated in 96 well TC plates at 2×10⁵ cells per wellin 50 μL of medium. 50 μL of two fold serial dilutions of test compounds(C_(max) is 10 μM) are added to each well (STI571 is included as apositive control). The cells are incubated for 90 minutes at 37° C., 5%CO₂. The cells are then treated for 1 hour on ice with 150 μL of lysisbuffer (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 5 mM EDTA, 1 mM EGTA and 1%NP-40) containing protease and phosphatase inhibitors. 50 μL of celllysate is added to 96 well optiplates previously coated with anti-ablspecific antibody and blocked. The plates are incubated for 4 hours at4° C. After washing with TBS-Tween 20 buffer, 50 μL ofalkaline-phosphatase conjugated anti-phosphotyrosine antibody is addedand the plate is further incubated overnight at 4° C. After washing withTBS-Tween 20 buffer, 90 μL of a luminescent substrate are added and theluminescence is quantified using the Acquest™ system (MolecularDevices). Test compounds of the invention that inhibit the proliferationof the BCR-Abl expressing cells, inhibit the cellular BCR-Ablautophosphorylation in a dose-dependent manner.

Effect on Proliferation of Cells Expressing Mutant Forms of Bcr-abl

Compounds of the invention are tested for their antiproliferative effecton Ba/F3 cells expressing either wild type or the mutant forms ofBCR-Abl (G250E, E255V, T315I, F317L, M351T) that confers resistance ordiminished sensitivity to STI571. The antiproliferative effect of thesecompounds on the mutant-BCR-Abl expressing cells and on the nontransformed cells were tested at 10, 3.3, 1.1 and 0.37 μM as describedabove (in media lacking IL3). The IC₅₀ values of the compounds lackingtoxicity on the untransformed cells were determined from the doseresponse curves obtained as describe above.

FGFR35 (Enzymatic Assay)

Kinase activity assay with purified FGFR35 (Upstate) is carried out in afinal volume of 104 containing 0.25 μg/mL of enzyme in kinase buffer (30mM Tris-HCl pH7.5, 15 mM MgCl₂, 4.5 mM MnCl₂, 15 μM Na₃VO₄ and 50 μg/mLBSA), and substrates (5 μg/mL biotin-poly-EY(Glu, Tyr) (CIS-US, Inc.)and 304 ATP). Two solutions are made: the first solution of 5 μlcontains the FGFR35 enzyme in kinase buffer was first dispensed into384-format ProxiPlate® (Perkin-Elmer) followed by adding 50 mL ofcompounds dissolved in DMSO, then 5 μl of second solution contains thesubstrate (poly-EY) and ATP in kinase buffer was added to each wells.The reactions are incubated at room temperature for one hour, stopped byadding 10 μL of HTRF detection mixture, which contains 30 mM Tris-HClpH7.5, 0.5 M KF, 50 mM ETDA, 0.2 mg/mL BSA, 15 μg/mL streptavidin-XL665(CIS-US, Inc.) and 150 ng/mL cryptate conjugated anti-phosphotyrosineantibody (CIS-US, Inc.). After one hour of room temperature incubationto allow for streptavidin-biotin interaction, time resolved florescentsignals are read on Analyst GT (Molecular Devices Corp.). IC₅₀ valuesare calculated by linear regression analysis of the percentageinhibition of each compound at 12 concentrations (1:3 dilution from 50μM to 0.28 nM). In this assay, compounds of the invention have an IC₅₀in the range of 10 nM to 2 μM.

FGFR35 (Cellular Assay)

Compounds of the invention are tested for their ability to inhibittransformed Ba/F3-TEL-FGFR35 cells proliferation, which is depended onFGFR35 cellular kinase activity. Ba/F3-TEL-FGFR35 are cultured up to800,000 cells/mL in suspension, with RPMI 1640 supplemented with 10%fetal bovine serum as the culture medium. Cells are dispensed into384-well format plate at 5000 cell/well in 50 μL culture medium.Compounds of the invention are dissolved and diluted in dimethylsufoxide(DMSO). Twelve points 1:3 serial dilutions are made into DMSO to createconcentrations gradient ranging typically from 10 mM to 0.05 μM. Cellsare added with 50 nL of diluted compounds and incubated for 48 hours incell culture incubator. AlamarBlue® (TREK Diagnostic Systems), which canbe used to monitor the reducing environment created by proliferatingcells, are added to cells at final concentration of 10%. Afteradditional four hours of incubation in a 37° C. cell culture incubator,fluorescence signals from reduced AlamarBlue® (Excitation at 530 nm,Emission at 580 nm) are quantified on Analyst GT (Molecular DevicesCorp.). IC₅₀ values are calculated by linear regression analysis of thepercentage inhibition of each compound at 12 concentrations.

Upstate KinaseProfiler™—Radio-enzymatic Filter Binding Assay

Compounds of the invention are assessed for their ability to inhibitindividual members of a panel of kinases (a partial, non-limiting listof kinases includes: Abl, BCR-Abl, BMX, FGFR35, Lck, JNK1, JNK2, CSK,RAF, MKK6 and P38). The compounds are tested in duplicates at a finalconcentration of 10 μM following this generic protocol. Note that thekinase buffer composition and the substrates vary for the differentkinases included in the “Upstate KinaseProfiler™” panel. The compoundsare tested in duplicates at a final concentration of 10 μM followingthis generic protocol. Note that the kinase buffer composition and thesubstrates vary for the different kinases included in the “UpstateKinaseProfiler™” panel. Kinase buffer (2.5 μL, 10×-containing MnCl₂ whenrequired), active kinase (0.001-0.01 Units; 2.5 μL), specific orPoly(Glu4-Tyr) peptide (5-500 μM or 0.01 mg/ml) in kinase buffer andkinase buffer (50 μM; 5 μL) are mixed in an eppendorf on ice. A Mg/ATPmix (10 μL; 67.5 (or 33.75) mM MgCl₂, 450 (or 225) μM ATP and 1 μCi/μl[γ-³²P]-ATP (3000Ci/mmol)) is added and the reaction is incubated atabout 30° C. for about 10 minutes. The reaction mixture is spotted (20μL) onto a 2 cm×2 cm P81 (phosphocellulose, for positively chargedpeptide substrates) or Whatman No. 1 (for Poly (Glu-4-Tyr) peptidesubstrate) paper square. The assay squares are washed 4 times, for 5minutes each, with 0.75% phosphoric acid and washed once with acetonefor 5 minutes. The assay squares are transferred to a scintillationvial, 5 ml scintillation cocktail are added and ³²P incorporation (cpm)to the peptide substrate is quantified with a Beckman scintillationcounter. Percentage inhibition is calculated for each reaction.

Compounds of Formula I**, in free form or in pharmaceutically acceptablesalt form, exhibit valuable pharmacological properties, for example, asindicated by the in vitro tests described in this application. Forexample, compounds of Formula I** preferably show an IC₅₀ in the rangeof 1×10⁻¹⁰ to 1×10⁻⁵M, preferably less than 50 nM for wild type BCR-Abland G250E, E255V, T315I, F317L and M351T BCR-Abl mutants. Compounds ofFormula I** preferably, at a concentration of 10 mM, preferably show apercentage inhibition of greater than 50%, preferably greater than about70%, against Abl, Bcr-abl, c-RAF, c-SRC, JNK2α2, lck, MKK6, PDGFRα,SAPK2α, SAPK2β, Tie2 and TrkB kinases. For example:N-(3-{3-[6-(3-Acetylamino-phenylamino)-pyrimidin-4-yl]-3-methyl-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide(Example 4) has an IC₅₀ of <0.5 nM, 38 nM, 44 nM, 41 nM, <0.5 nM and<0.5 nM for wild type, G250E, E255V, T315I, F317L and M351T Bcr-abl,respectively;

b).N-{3-[3-(6-Amino-pyrimidin-4-yl)-3-(2-morpholin-4-yl-ethyl)-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide(Example 214) has an IC50 of 65 nM and 49 nM for the FGFR35 enzyme andcellular assays, respectively, and 14.9 nM and 0.4 nM for Bcr-abl wildtype and PDGFRβ, respectively;

c). N-(3-{3-(6-Amino-pyrimidin-4-yl)-3-[3-(2 oxopyrrolidin-1-yl)-propyl]-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide(Example 215) has an IC50 of 16 nM and 15 nM for the FGFR35 enzyme andcellular assays, respectively, and 10 nM and 2 nM for Bcr-abl wild typeand PDGFRβ, respectively;

d).N-(3-{3-(6-Amino-pyrimidin-4-yl)-3-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-ureido}-4-methyl-phenyl)-3-trifluoromethyl-benzamide(Example 215), at a concentration of 10 μM, inhibits the followingkinases by the percentage shown in brackets (for example, 100% meanscomplete inhibition, 0% means no inhibition): wild-type Abl (99%), c-RAF(99%), CSK (97%), c-SRC (100%), FGFR35 (99%), INK2 cc2 (93%), lck(100%), MKK6 (88%), p70S6K (81%), ROS (95%), SAPK2α (99%), SAPK2β (99%),Tie2 (100%) and TrkB (99%). It is understood that the examples andembodiments described herein are for illustrative purposes only and thatvarious modifications or changes in light thereof will be suggested topersons skilled in the art and are to be included within the spirit andpurview of this application and scope of the appended claims. Allpublications, patents, and patent applications cited herein are herebyincorporated by reference for all purposes.

Example 2171-(2,6-Dichloro-3,5-dimethoxy-Phenyl)-3-{6-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

The title compound is prepared as described in Example 160 but usingN-[4-(4-isopropyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine (385mg, 1.23 mmol, 1 eq.), and stirring the reaction mixture for 0.5 h at70° C. The title compound: ESI-MS: 560.0/562.0 [MH]⁺; t_(R)=3.17 min(purity: 98%, gradient J); TLC: R_(f)=0.31 (DCM/MeOH+1% NH₃ ^(aq),95:5).

A. N-[4-(4-Isopropyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 144A but using4-(4-isopropyl-piperazin-1-yl)-phenylamine (400 mg, 1.83 mmol, 1 eq.),6-chloro-pyrimidin-4-yl)-amine (1.3 eq.), and stirring the reactionmixture at 150° C. for 18 h. Purification of the crude product bytrituration in diethyl ether affords the title compound as a whitesolid: ESI-MS: 313.2 [MH]⁺; t_(R)=1.00 min (gradient J).

B. 4-(4-Isopropylpiperazin-1-yl)-aniline

A suspension of 1-isopropyl-4-(4-nitro-phenyl)-piperazine (5.18 g, 20.80mmol) and Palladium (5%) on carbon (0.5 g) in MeOH (100 mL) is stirredfor 2.7 h at RT, under a hydrogen atmosphere. The reaction mixture isfiltered through a pad of celite and concentrated to afford the titlecompound as a violet solid: ESI-MS: 220.1 [MH]⁺; t_(R)=0.95 min(gradient J).

C. 1-Isopropyl-4-(4-nitro-phenyl)-piperazine

A mixture of 1-bromo-4-nitrobenzene (6 g, 29.7 mmol) and1-ethylpiperazine (7.6 ml, 59.4 mmol, 2 eq.) is heated to 80° C. for 15h. After cooling to RT, the reaction mixture is concentrated.Purification of the residue by silica gel column chromatography(DCM/MeOH , 95:5) affords 5.18 g of the title compound as a yellowsolid: ESI-MS: 250.1 [MH]°; t_(R)=2.57 min (purity: 100%, gradient J);TLC: R_(f)=0.16 (DCM/MeOH , 95:5).

Example 2183-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-(6-{4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenylamino}-pyrimidin-4-yl)-urea

The title compound is prepared as described in Example 144 but usingN-{4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenyl}-pyrimidine-4,6-diamine(227 mg, 1.23 mmol, 1 eq.), and stirring the reaction mixture for 18 hat 70° C. Purification of the crude product by silica gel columnchromatography (DCM/MeOH+1% NH₃ ^(aq), 95:5) affords the title compoundas a white solid: ESI-MS: 589.9/591.9 [MH]⁺; t_(R)=3.11 min (purity:100%, gradient J); TLC: R_(f)=0.12 (DCM/MeOH+1% NH₃ ^(aq), 95:5).

A.N-Methyl-N′-{4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenyl}-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 160A but using4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenylamine (500 mg, 2.13 mmol, 1eq.), (6-chloro-pyrimidin-4-yl)-ethyl-amine and stirring the reactionmixture at 150° C. for 20 h. Purification of the crude product by silicagel column chromatography (DCM/MeOH+1% NH₃ ^(aq), 9:1) followed bytrituration in diethyl ether affords 250 mg of the title compound as awhite solid: ESI-MS: 343.2 [MH]⁺; t_(R)=1.00 min (gradient J); TLC:R_(f)=0.23 (DCM/MeOH+1% NH₃ ^(aq), 9:1).

Example 2193-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-isopropyl-Piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea

The title compound is prepared as described in Example 144 but usingN-[4-(4-isopropyl-piperazin-1-yl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine(1.71 g, 5.25 mmol, 1 eq.) and performing the reaction mixture for 45min at reflux. Purification of the crude product by trituration in MeOHfollowed by silica gel column chromatography (DCM/MeOH+1% NH₃ ^(aq),97:3) affords the title compound as a white solid: ESI-MS: 573.9/575.9[MH]⁺: t_(R)=3.65 min (purity: 100%, gradient J); TLC: R_(f) 0.10(DCM/MeOH+1% NH₃ ^(aq), 97:3).

A.N-[4-(4-Isopropyl-piperazin-1-yl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 144A but using4-(4-isopropylpiperazin-1-yl)-aniline (Example 2178) (2.6 g, 11.9 mmol).Purification of the residue by silica gel column chromatography(DCM/MeOH, 93:7) affords 1.71 g of the title compound as a white solid:ESI-MS: 327.2 [MH]⁺; t_(R)=1.30 min (gradient J); TLC: R_(f) 0.26(DCM/MeOH, 93:7).

Example 2201-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-[6-(4-dimethylaminomethyl-3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-urea

The title compound is prepared as described in Example 144 but usingN-(4-dimethylaminomethyl-3-trifluoromethyl-phenyl)-pyrimidine-4,6-diamine(250 mg, 0.80 mmol, 1 eq.), 2 eq. of isocyanate, and performing thereaction mixture for 30 min at reflux. Purification of the crude productby silica gel column chromatography (DCM/MeOH+1% NH₃ ^(aq), 95:5)affords the title compound as a white solid: ESI-MS: 558.9/560.9 [MH]⁺;t_(R)=3.69 min (purity: 100%, gradient J); TLC: R_(f)=0.21 (DCM/MeOH+1%NH₃ ^(aq), 95:5).

A.N-(4-Dimethylaminomethyl-3-trifluoromethyl-phenyl)-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 144A but using4-dimethylaminomethyl-3-trifluoromethyl-phenylamine (300 mg, 1.46 mmol)and 6-chloro-pyrimidin-4-yl)-amine (1.3 eq.). Purification of the crudeproduct by silica gel column chromatography (DCM/MeOH, 93:7) affords thetitle compound as a white solid: ESI-MS: 312.1 [MH]⁺; TLC: R_(f)=0.16(DCM/MeOH, 93:7).

Example 1643-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(4-dimethylaminomethyl-3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-1-methyl-urea

The title compound is prepared as described in Example 144 but usingN-(4-dimethylaminomethyl-3-trifluoromethyl-phenyl)-N′-methyl-pyrimidine-4,6-diamine(200 mg, 0.62 mmol, 1 eq.), and performing the reaction mixture for 1 hat reflux. Purification of the crude product by trituration in MeOHfollowed by silica gel column chromatography (DCM/MeOH+1% NH₃ ^(aq),95:5) affords the title compound as a white solid: ESI-MS: 572.8 /574.8[MH]⁺; t_(R)=4.14 min (purity: 100%, gradient J); TLC: R_(f)=0.24(DCM/MeOH+1% NH₃ ^(aq), 95:5).

A.N-(4-Dimethylaminomethyl-3-trifluoromethyl-phenyl)-N′-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 144A but using4-dimethylaminomethyl-3-trifluoromethyl-phenylamine (300 mg, 1.46 mmol)and 1.3 eq. of 6-chloro-pyrimidin-4-yl)-methyl-amine. Purification ofthe crude product by silica gel column chromatography (DCM/MeOH, 93:7)affords the title compound as a white solid: ESI-MS: 326.1 [MH]⁺; TLC:R_(f)=0.27 (DCM/MeOH, 93:7).

Example 2223-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-(6-(3-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-phenylamino)-pyrimidin-4-yl]-1-methyl-urea

The title compound is prepared as described in Example 144 but usingN-(3-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-pyrimidine-4,6-diamine(250 mg, 0.80 mmol, 1 eq.), 1.5 eq. of isocynaze, and performing thereaction mixture for 6 h at reflux. Purification of the crude product byMPLC (by silica gel) (DCM/MeOH+1% NH₃ ^(aq), 95:5) followed bytrituration in diethyl ether affords the title compound as a whitesolid: ESI-MS: 561.9/563.9 [MH]⁺; t_(R)=3.24 min (purity: 100%, gradientJ); TLC: R_(f)=0.10 (DCM/MeOH+1% NH₃ ^(aq), 9:1).

A.N-(3-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-N′-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 144A but usingN-(3-amino-benzyl)-N,N′,N′-trimethyl-ethane-1,2-diamine (500 mg, 2.41mmol), 1.1 eq. of 6-chloro-pyrimidin-4-yl)-methyl-amine, and stirringthe reaction mixture for 17.5 h. Purification of the crude product bysilica gel column chromatography (DCM/MeOH+1% NH₃ ^(aq), 95:5) affordsthe title compound as a beige solid: ESI-MS: 315.2 [MH]⁺; TLC:R_(f)=0.05 (DCM/MeOH+1% NH₃ ^(aq), 9:1).

B. N-(3-Amino-benzyl)-N,N′,N′-trimethyl-ethane-1,2-diamine

A suspension of N,N′,N′-trimethyl-N′-(3-nitro-benzyl)-ethane-1,2-diamine(4.5 g, 18.96 mmol) and Raney Nickel (1.2 g) in MeOH (100 mL) is stirredfor 2 h at RT, under a hydrogen atmosphere. The reaction mixture isfiltered through a pad of celite and concentrated to afford the titlecompound as a yellow oil: ESI-MS: 208.2.

C. N,N′,N′-Trimethyl-N′-(3-nitro-benzyl)-ethane-1,2-diamine

A mixture of 3-nitrobenzylchloride (4.5 g, 26.23 mmol),N,N,N-trimethylethylendiamine (4.1 ml, 31.47 mmol, 1.2 eq.), potassiumcarbonate (7.3 g, 52.46, 2 eq.), and acetone (90 ml) is stirred for 19 hat 80° C. The reaction mixture is allowed to cool to RT, filtered andconcentrated. Purification of the crude product by silica gel columnchromatography (DCM/MeOH+1% NH₃ ^(aq), 9:1) affords the title compoundas a brown oil: ESI-MS: 238.1 [MH]⁺; t_(R)=1.10 min (gradient J); TLC:R_(f)=0.10 (DCM/MeOH+1% NH₃ ^(aq), 9:1).

Example 2233-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[3-(4-isopropyl-piperazin-1-ylmethyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea

The title compound is prepared as described in Example 144 but usingN-[3-(4-isopropyl-piperazin-1-ylmethyl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine(250 mg, 0.73 mmol, 1 eq.). Purification of the crude product by MPLC(silica gel) (DCM/MeOH+1% NH₃ ^(aq), 95:5) followed by trituration indiethyl ether affords the title compound as a white solid: ESI-MS:587.9/589.9 [MH]⁺; t_(R)=3.35 min (purity: 100%, gradient J); TLC:R_(f)=0.17 (DCM/MeOH+1% NH₃ ^(aq), 9:1).

A.N-[3-(4-Isopropyl-piperazin-1-ylmethyl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 143A but using3-(4-isopropyl-piperazin-1-ylmethyl)-phenylamine (500 mg, 2.14 mmol, 1eq.) and stirring the reaction mixture for 17.5 h at 150° C.Purification of the crude product by MPLC (silica gel) (DCM/MeOH+1% NH₃^(aq), 95:5) affords the title compound as a light yellow solid: TLC:R_(f)=0.10 (DCM/MeOH+1% NH₃ ^(aq), 9:1).

B. 3-(4-Isopropyl-piperazin-1-ylmethyl)-phenylamine

The title compound is prepared as described in Example 149B: ESI-MS:234.1 [MH]⁺; t_(R)=0.95 min (gradient J).

C. 1-Isopropyl-4-(3-nitro-benzyl)-piperazine

The title compound is prepared as described in Example 222C: ESI-MS:264.1 [MH]⁺; TLC: R_(f)=0.35 (DCM/MeOH+1% NH₃ ^(aq), 9:1).

Example 2241-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[3-(1-methyl-piperidin-4-yloxy)-phenylamino]-pyrimidin-4-yl}-urea

The title compound is prepared as described in Example 160 but usingN-[3-(1-methyl-piperidin-4-yloxy)-phenyl]-pyrimidine-4,6-diamine (205mg, 0.69 mmol, 1 eq.). Purification of the crude product by silica gelcolumn chromatography (DCM/MeOH+1% NH₃ ^(aq), 95:5) followed bytrituration in MeOH affords the title compound as a white solid: ESI-MS:546.9 /548.9 [MH]⁺; t_(R)=3.14 min (purity: 100%, gradient J); TLC:R_(f)=0.13 (DCM/MeOH+1% NH₃ ^(aq), 95:5).

A. N-[3-(1-Methyl-piperidin-4-yloxy)-phenyl]-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 160A but using3-(1-methyl-piperidin-4-yloxy)-phenylamine (500 mg, 2.43 mmol, 1 eq.)and stirring the reaction mixture for 20 h at 100° C. Trituration of thecrude product in EE affords the title compound as a red solid: ESI-MS:300.2 [MH]⁺; t_(R)=0.85 min (gradient J).

B. 3-(1-Methyl-piperidin-4-yloxy)-phenylamine

The title compound is prepared as described in Example 217B: ESI-MS:207.1 [MH]⁺.

C. 1-Methyl-4-(3-nitro-phenoxy)-piperidine

A mixture of 4-fluoro-nitrobenzene (10 g, 71.0 mmol),4-hydroxy-1-methyl-piperidine (16.6 ml, 141.8 mmol, 2 eq.),tetrabutylammonium bromide (4.6 g, 14.2 mmol, 0.2 eq.), toluene (50 ml)and a 25% aqueous solution of potassium hydroxide (50 ml) is stirred for15 h at 60° C. The reaction mixture is cooled to RT and poured ontoice/water. The resulting suspension is filtered and the filtrate isextracted with EE. The organic phase is washed with 0.5 N HCl, brine,then dried (sodium sulfate), filtered, and concentrated to afford 6 g ofthe title compound. The aqueous layer is made neutral by addition ofsodium bicarbonate and extracted with EE. The organic phase is washedwith brine, dried (sodium sulfate), filtered, and concentrated to affordadditional 10 g of the title compound: ESI-MS: 237.0 [MH]⁺; t_(R)=2.61min (purity: 90%, gradient J).

Example 2253-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-{6-[3-(1-methyl-piperidin-4-yloxy)-phenylamino]-pyrimidin-4-yl}-urea

The title compound is prepared as described in Example 144 but usingN-methyl-N′-[3-(1-methyl-piperidin-4-yloxy)-phenyl]-pyrimidine-4,6-diamine(130 mg, 0.41 mmol, 1 eq.). Purification of the crude product by silicagel column chromatography (DCM/MeOH+1% NH₃ ^(aq), 95:5) followed bytrituration in MeOH affords the title compound as a white solid: ESI-MS:561.0/563.0 [MH]⁺; t_(R)=3.66 min (purity: 97%, gradient J).

A.N-Methyl-N′-[3-(1-methyl-piperidin-4-yloxy)-phenyl]-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 160A but using3-(1-methyl-piperidin-4-yloxy)-phenylamine (Example 224B). The titlecompound as a red solid: ESI-MS: 314.2 [MH]⁺; TLC: R_(f)=0.16(DCM/MeOH+1% NH₃ ^(aq), 9:1).

Example 2263-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-diethylaminomethyl-phenylamino)-pyrimidin-4-yl]-1-methyl-urea

The title compound is prepared as described in Example 144 but usingN-(3-diethylaminomethyl-phenyl)-N′-methyl-pyrimidine-4,6-diamine (128mg, 0.45 mmol, 1 eq.). The title compound: ESI-MS: 533.0/535.0 [MH]⁺;t_(R)=3.94 min (purity: 100%, gradient J); TLC: R_(f)=0.37 (DCM/MeOH+1%NH₃ ^(aq), 92:8).

A. N-(3-Diethylaminomethyl-phenyl)-N′-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 144A but using3-diethylaminomethyl-phenylamine. The title compound: ESI-MS: 286.1[MH]⁺; TLC: R_(f)=0.05 (DCM/MeOH+1% NH₃ ^(aq), 9:1).

B. 3-Diethylaminomethyl-phenylamine

The title compound is prepared as described in Example 149B but usingdiethyl-(3-nitrobenzyl)-amine. The title compound contains 30% of3-methyl-aniline and is used as a crude impure material.

C. Diethyl-(3-nitrobenzyl)-amine

The title compound is prepared as described in Example 149C but usingdiethylamine. The title compound: t_(R)=1.83 min (purity: 100%, gradientJ); TLC: R_(f)=0.38 (DCM/MeOH, 9:1).

Example 2273-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{4-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,3,5]triazin-2-yl}-urea

To a solution of 2,6-dichloro-3,5-dimethoxy-aniline (124 mg , 0.56 mmol;Preparation 2) in 2 ml of dioxane under a nitrogene atmosphere, phosgene(0.52 ml 20% in toluene, 0.98 mmol) is added. The mixture is stirred for70 min at 100° C., cooled to RT and concentrated in vacuo, yielding2,6-dichloro-3,5-dimethoxyphenylisocyanate.

The resulting solid is added portion-wise to a boiling solution ofN-methyl-N′-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,3,5]triazine-2,4-diamine(140 mg, 0.47 mmol) in 8 ml of toluene during 20 min. After 3 h, another2 eq of 2,6-dichloro-3,5-dimethoxyphenylisocyanate are added andstirring is continued for totally 5 h. Then the reaction mixture isdiluted with DCM and a saturated aqueous solution of NaHCO₃. The aqueouslayer is separated and extracted twice with DCM. The organic phases arewashed with water and brine, dried (Na₂SO₄) and concentrated. Columnchromatography (SiO₂; DCM/MeOH/NH₃ ^(aq) 97:3:0.2) gives the titlecompound: ESI-MS: 547/549 [MH]⁺; t_(R)=3.5 min (purity: 100%, gradientJ); TLC: R_(f)=0.40 (DCM/MeOH+1% NH₃ ^(aq), 95:5).

A.N-Methyl-N′-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,3,5]triazine-2,4-diamine

A solution of (4-chloro-[1,3,5]triazin-2-yl)methyl-amine (290 mg, 2.00mmol) and 4-(4-methylpiperazin-1-yl)-aniline (570 mg, 3.0 mmol) in EtOH(20 ml) and N-ethyl-diisopropyl amine (530 μl, 3.1 mmol) is heated to80° C. for 2 h under a nitrogen atmosphere. The reaction mixture isconcentrated and the residue re-dissolved in EE and water. The separatedoff aqueous phase is extracted twice with EE, the organic layer washedwith water and brine, dried (Na₂SO₄) and concentrated. Columnchromatography (SiO₂; DCM/MeOH/NH₃ ^(aq) 95:5:0.2) gives the titlecompound: TLC: R_(f)=0.07 (DCM/MeOH+1 NH₃ ^(aq), 95:5).

B. (4-Chloro-[1,3,5]triazin-2-yl)-methyl-amine

To an ice cooled solution of 2,4-dichlor-[1,3,5]triazine (2.25 g, 15mmol; WO 2004/072063, Expl. 9) in 20 ml of THF, MeNH₂ (15 ml of 2 Msolution in THF) is added. After 1 h the mixture is diluted with 15 mlof water and concentrated partially in vacuo. The precipitated titlecompound can be filtered off, washed with ice-water and dried: ESI-MS:143 [M−H.

Example 2283-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{4-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-[1,3,5]triazin-2-yl}-urea

To a solution of 2,6-dichloro-3,5-dimethoxy-anilin (133 mg , 0.60 mmol;Preparation 2) in 2 ml of dioxane under a nitrogen atmosphere, phosgene(0.54 ml 20% in toluene, 1.0 mmol) is added. The mixture is stirred for60 min at 100° C., cooled to RT and concentrated in vacuo, yielding2,6-dichloro-3,5-dimethoxyphenylisocyanate. The resulting solid is addedportion-wise to a boiling solution ofN-methyl-N′-[4-(4-ethyl-piperazin-1-yl)-phenyl]-[1,3,5]triazine-2,4-diamine(156 mg, 0.50 mmol) in 7 ml of toluene during 15 min. After 5 h, thereaction mixture is diluted with DCM and a saturated aqueous solution ofNaHCO₃. The aqueous layer is separated and extracted twice with DCM. Theorganic phases are washed with water and brine, dried (Na₂SO₄) andconcentrated. Column chromatography (SiO₂; DCM/MeOH/NH₃ ^(aq) 95:5:0.2)gives the title compound: ESI-MS: 561 /563 [MH]⁺; t_(R)=3.6 min(gradient J); TLC: R_(f)=0.4 (DCM/MeOH+1% NH₃ ^(aq), 95:5).

A.N-Methyl-N′-[4-(4-ethyl-piperazin-1-yl)-phenyl]-[1,3,5]triazine-2,4-diamine

A mixture of (4-chloro-[1,3,5]triazin-2-yl)-methyl-amine (290 mg, 2.00mmol), NaI (28 mg) and 4-(4-ethylpiperazin-1-yl)-aniline (410 mg, 2.0mmol) in EtOH (20 ml) and N-ethyl-diisopropyl amine (350 μl, 2.0 mmol)is heated to 80° C. for 3 h under a nitrogen atmosphere. The reactionmixture is cooled to RT, concentrated partially in vacuo and dilutedwith hexane at 0° C. The precipitate is filtered off, washed with Et₂Oand re-dissolved in EE and water. The separated off aqueous phase isextracted twice with EE, the organic layer washed with water and brine,dried (Na₂SO₄) and concentrated, yielding the title compound: ESI-MS:314 [MH]⁺; TLC: R_(f)=0.10 (DCM/MeOH 9:1).

Example 2293-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1-{4-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-[1,3,5]triazin-2-yl}-urea

To a solution ofN-methyl-N′-[4-(4-ethyl-piperazin-1-yl)-phenyl]-[1,3,5]triazine-2,4-diamine(24 mg, 0.077 mmol) in 1.5 ml THF and 2.5 ml toluene,4-fluoro-3-trifluoromethyl-phenyl-isocyanate (25 μl, 0.17 mmol) is addedand the mixture is stirred for 5 h at 100° C. Workup analogously asdescribed in Example 171 gives the title compound: ESI-MS: 519 [MH]⁺;t_(R)=4.3 min (purity: 100%, gradient J); TLC: R_(f)=0.43 (DCM/MeOH 9).

Example 2303-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{4-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-[1,3,5]triazin-2-yl}-urea

As described in Example 230, 2,6-dichloro-3,5-dimethoxy-aniline (133 mg, 0.60 mmol; Preparation 2) andN-methyl-N′-[4-(4-isopropyl-piperazin-1-yl)-phenyl]-[1,3,5]triazine-2,4-diamine(163 mg, 0.50 mmol) are converted to the title compound: ESI-MS: 575/577[MH]⁺; t_(R)=3.7 min (gradient J); TLC: R_(f)=0.32 (DCM/MeOH+1% NH₃^(aq), 95:5).

A.N-Methyl-N′-[4-(4-isopropyl-piperazin-1-yl)-phenyl]-[1,3,5]triazine-2,4-diamine

A mixture of (4-chloro-[1,3,5]triazin-2-yl)methyl-amine (290 mg, 2.00mmol), NaI (28 mg) and 4-(4-propylpiperazin-1-yl)-aniline (500 mg, 2.0mmol) in EtOH (20 ml) and N-ethyl-diisopropyl amine (350 μl, 2.0 mmol)is heated to 80° C. for 3 h under a nitrogen atmosphere. Workup asdescribed in Example 228A gives the title compound: ESI-MS: 328 [MH]⁺;TLC: R_(f)=0.14 (DCM/MeOH, 9:1).

Example 2313-(2,6-Dichloro-3-trifluoromethyl-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea

To a solution of 2,6-dichloro-3-trifluoromethyl-aniline (138 mg , 0.60mmol) in 2 ml of dioxane under a nitrogen atmosphere, phosgene (0.54 ml20% in toluene, 1.0 mmol) is added. The mixture is stirred for 2 h at100° C., cooled to rt and concentrated in vacuo, yielding2,6-dichloro-3-trifluoromethyl-phenylisocyanate.

This oil is re-dissolved in 2 ml of toluene and added portion-wise to aboiling solution ofN-[4-(4-ethyl-piperazin-1-yl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine(156 mg, 0.50 mmol; Example 145A) in 6 ml of toluene during 10 min.After 1.5 h, another 2 eq of2,6-dichloro-3-trifluoromethyl-phenylisocyanate are added and stirringis continued for totally 2 h. Then the reaction mixture is diluted withDCM and a saturated aqueous solution of NaHCO₃. The aqueous layer isseparated and extracted twice with DCM. The organic phases are washedwith water and brine, dried (Na₂SO₄) and concentrated. Columnchromatography (SiO₂; CH₂Cl₂/MeOH/NH₃ ^(aq) 95:5:0.5) gives the titlecompound: ESI-MS: 568/570 [MH]⁺; t_(R)=4.1 min (gradient J); TLC:R_(f)=0.3 (DCM/MeOH+1% NH₃ ^(aq), 95:5).

A. 2,6-Dichloro-3-trifluoromethyl-anilin

Hydrogenation of 2,4-dichloro-3-nitro-benzotrifluorid (5.0 g, 19.2 mmol;ABCR, Karlsruhe/Germany) in 100 ml MeOH in the presence of 1 gRaney-nickel, filtration and concentration of the filtrate gives thetitle compound: TLC: R_(f)=0.67 (EE).

1. A process for the preparation of a compound of formula (I):

wherein the following fragment is referred to as the “left hand ring”

the left hand ring wherein X¹ is oxygen, X is C—R⁵, R⁵ is H, R² is H,and Y and Z are both N, whereby the left hand ring has the structure ofFragment (B):

wherein R¹ is of the formula R^(z)—NR^(a)— wherein R^(a) is hydrogen;and R^(z) is

a group of the formula where: ring A represents a 6-membered carbocyclicor heterocyclic ring; m is 0, 1 or 2; the or each R^(b) is independentlyselected from -L²-NR^(c)R^(d); -L²-RING where RING is a mono- orbi-cyclic ring optionally substituted as defined below; halogen;hydroxy; protected hydroxyl; amino; amidino; guanidino;hydroxyguanidino; formamidino; isothioureido; ureido; mercapto; acylhaving 4 in-chain atoms; acyloxy having 4 in-chain atoms; carboxy;sulfo; sulfamoyl; carbamoyl; cyano; azo; or nitro; and linear orbranched alkyl having 1, 2, 3 or 4 carbon atoms optionally substitutedby one or more halogens and/or one or two functional groups selectedfrom hydroxy, protected hydroxy, amino, amidino, guanidino,hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, acylhaving 4 in-chain atoms, acyloxy having 4 in-chain atoms, carboxy,sulfo, sulfamoyl, carbamoyl, cyano, azo, or nitro; all of which hydroxy,amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido,ureido, mercapto, carboxy, sulfo, sulfamoyl, carbamoyl and cyano groupsare in turn optionally substituted on at least one heteroatom by one or,where possible, more C₁-C₇ aliphatic groups, wherein L² is a directbond; a linkage selected from —O—; —S—; —C(O)—; —OC(O)—; —NR^(a)C(O)—;—C(O)—NR^(a)—; —OC(O)—NR^(a)—; cyclopropyl and —NR^(a)—; or is a linearor branched alkyl group having 1, 2, 3 or 4 carbon atoms optionallyinterrupted and/or terminated at a single end or at both ends by a saidlinkage; and wherein R^(c) and R^(d) are each independently selectedfrom hydrogen, and linear or branched alkyl having 1, 2, 3 or 4 carbonatoms optionally substituted by one or more halogens, by an optionallysubstituted 5- or 6-membered heterocyclic or carbocyclic ring, and/orone or two functional groups selected from hydroxy, protected hydroxy,amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido,ureido, mercapto, acyl having 4 in-chain atoms, acyloxy having 4in-chain atoms, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, ornitro, which hydroxy, amino, amidino, guanidino, hydroxyguanidino,formamidino, isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl,carbamoyl and cyano groups are in turn optionally substituted on atleast one heteroatom by one or more C₁-C₇ aliphatic groups, or R^(c) andR^(d) together with their adjoining nitrogen form a 5- or 6-memberedring optionally substituted as described below, said optionallysubstituted rings independently of each other being substituted by 0, 1,2, 3, 4 or 5 substituents selected from halogen; hydroxy; protectedhydroxy; amino; amidino; guanidino; hydroxyguanidino; formamidino;isothioureido; ureido; mercapto; acyl having 4 in-chain atoms; acyloxyhaving 4 in-chain atoms; carboxy; sulfo; sulfamoyl; carbamoyl; cyano;azo; nitro; C₁-C₇ aliphatic optionally substituted by one or morehalogens and/or one or two functional groups selected from hydroxy,protected hydroxy, amino, amidino, guanidino, hydroxyguanidino,formamidino, isothioureido, ureido, mercapto, acyl having 4 in-chainatoms, acyloxy having 4 in-chain atoms, carboxy, sulfo, sulfamoyl,carbamoyl, cyano, azo, or nitro; all of the aforesaid hydroxy, amino,amidino, guanidino, hydroxyguanidino, formamidino, isothioureido,ureido, mercapto, carboxy, sulfo, sulfamoyl and carbamoyl groups in turnoptionally being substituted on at least one heteroatom by one or, wherepossible, more C₁-C₇ aliphatic groups; R³ is H, a straight chain orbranched C₁-C₄ alkyl or a straight chain or branched C₁-C₄ alkylsubstituted by a 5- or 6-membered saturated or unsaturated carbocyclicor heterocyclic ring; or pharmaceutically acceptable salts, hydrates,solvates, esters, N-oxides, protected derivatives, individualstereoisomers and mixture of stereoisomers thereof; said processcomprising, a) reacting 4,6-Dichloropyrimidine,

with a compound of formula R³NH₂ to provide a compound of formula:

b) reacting said compound of formula:

with a compound of formula R^(z)NH₂ to provide a compound of formula:

and then, b) reacting said compound of formula:

with 2,6-dichloro-3,5-dimethoxyphenylisocyanate.
 2. The processaccording to claim 1, wherein said2,6-dichloro-3,5-dimethoxyphenylisocyanate is obtained by reacting2,6-dichloro-3,5-dimethoxyaniline with phosgene (COCl₂).
 3. The processaccording to claim 1, wherein the left hand ring has a structurecorresponding to Fragment (D1), (D2), (E1) or (E2):


4. The process according to claim 3, wherein the phenyl ring of saidFragments has 1, 2, 3 or 4 further substituents, selected from halogen,methyl, methoxy and trifluoromethyl.
 5. The process according to claim 1wherein RING is a saturated heterocycle which contains an in-ringnitrogen.
 6. The process according to claim 1 in which the compound offormula (I) contains a moiety NR^(c)R^(d) and wherein R^(c) and R^(d)are the same or different and selected from straight chain or branchedalkyl having 1, 2, 3 or 4 carbon atoms.
 7. The process according toclaim 1 in which the compound of formula (I) contains a moietyNR^(c)R^(d) and wherein R^(c) and R^(d) together with the adjoiningnitrogen form a 5- or 6-membered heterocyclic ring, optionallysubstituted as by 0, 1, 2, 3, 4 or 5 substituents selected from straightchain or branched C₁, C₂, C₃ or C₄ alkyl, halogen and C₁, C₂, C₃ or C₄alkoxy, wherein alkyl and the alkyl part of alkoxy are unsubstituted orsubstituted by halogen.
 8. The process according to claim 7 whereinL²NR^(c)R^(d) is selected from -Pip, -Morph, —OCH₂Pip, —OCH₂-Morph,—OCH₂CH₂Pip, —OCH₂CH₂-Morph, —OCH₂CH₂CH₂Pip, —OCH₂CH₂CH₂-Morph, —CH₂Pip,—CH₂-Morph, —CH₂CH₂Pip, —CH₂CH₂-Morph, —CH₂CH₂CH₂Pip, —CH₂CH₂CH₂-Morph,—C(O)Pip and —C(O)Morph, where “Pip” stands for piperazine and “Morph”for morpholine, piperazine optionally being N-substituted by straightchain or branched C₁, C₂, C₃ or C₄ alkyl.
 9. The process according toclaim 3 wherein the left hand ring has the structure of the followingFragment (F):


10. The process according to claim 1, wherein the compound according toformula (I) is selected from:3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-ethyl-1-{6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-pyrimidin-4-yl}-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-ethyl-1-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-dimethylaminomethyl-phenylamino)-pyrimidin-4-yl]-1-methyl-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-(6-{4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenylamino}-pyrimidin-4-yl)-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(3-dimethylamino-propyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[3-(4-ethyl-piperazin-1-ylmethyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-dimethylaminomethyl-phenylamino)-pyrimidin-4-yl]-1-ethyl-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(2,6-dimethyl-pyridin-3-ylamino)-pyrimidin-4-yl]-1-methyl-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyrimidin-4-yl]-urea;1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-ethyl-1-{6-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea;1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-[6-(3-dimethylaminomethyl-phenylamino)-pyrimidin-4-yl]-urea;1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-(6-{4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenylamino}-pyrimidin-4-yl)-urea;1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-[6-(4-dimethylaminomethyl-3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-urea;1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[3-(4-isopropyl-piperazin-1-ylmethyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-phenylamino)-pyrimidin-4-yl]-1-methyl-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea;1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(1-methyl-piperidin-4-yloxy)-phenylamino]-pyrimidin-4-yl}-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-{6-[4-(1-methyl-piperidin-4-yloxy)-phenylamino]-pyrimidin-4-yl}-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-ethyl-{6-[4-(1-methyl-piperidin-4-yloxy)-phenylamino]-pyrimidin-4-yl}-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(4-dimethylaminomethyl-3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-1-methyl-urea;1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamino]-pyrimidin-4-yl}-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamino]-pyrimidin-4-yl}-methyl-urea;1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-(6-{4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenylamino}-pyrimidin-4-yl)-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea;1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-[6-(4-dimethylaminomethyl-3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(4-dimethylaminomethyl-3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-1-methyl-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-phenylamino)-pyrimidin-4-yl]-1-methyl-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[3-(4-isopropyl-piperazin-1-ylmethyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea;1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[3-(1-methyl-piperidin-4-yloxy)-phenylamino]-pyrimidin-4-yl}-urea;3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-{6-[3-(1-methyl-piperidin-4-yloxy)-phenylamino]-pyrimidin-4-yl}-urea;and3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-diethylaminomethyl-phenylamino)-pyrimidin-4-yl]-1-methyl-urea.11. The process according to claim 10, wherein the compound according toformula (I) is3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea.12. The process according to claim 10, wherein the compound according toformula (I) is1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea.13. The process according to claim 1, wherein the compound according toformula:

isN-[4-(4-ethyl-piperazin-1-yl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine.14. The compound 2,6-dichloro-3,5-dimethoxyaniline.
 15. The compound2,6-dichloro-3,5-dimethoxyphenylisocyanate.
 16. The compoundN-[4-(4-ethyl-piperazin-1-yl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine.